Methods for making oxidation resistant polymeric material

ABSTRACT

The present invention relates to methods for making oxidation resistant medical devices that comprise polymeric materials, for example, ultra-high molecular weight polyethylene (UHMWPE). The invention also provides methods of making antioxidant-doped medical implants, for example, doping of medical devices containing cross-linked UHMWPE with vitamin E by diffusion, post-doping annealing, and materials used therein.

This application claims the benefit of U.S. Provisional Application Ser.No. 60/569,624, filed May 11, 2004, which is incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to methods for making oxidation resistantmedical devices that comprise polymeric materials. Methods of dopingpolyethylene with an antioxidant (for example, vitamin E) post-dopingannealing, and materials used therewith also are provided.

BACKGROUND OF THE INVENTION

Oxidation resistant cross-linked polymeric material, such as ultra-highmolecular weight polyethylene (UHMWPE), is desired in medical devicesbecause it significantly increases the wear resistance of the devices.The preferred method of crosslinking is by exposing the UHMWPE toionizing radiation. However, ionizing radiation, in addition tocrosslinking, also will generate residual free radicals, which are theprecursors of oxidation-induced embrittlement. Melting during or afterirradiation has been used to eliminate the crystals and allow theresidual free radicals to recombine with each other. The irradiationwith subsequent melting is used to reduce the potential for oxidationsecondary to the residual free radicals. However, such melting reducesthe crystallinity of UHMWPE, which, in turn, decreases the yieldstrength, ultimate tensile strength, modulus, and fatigue strength ofUHMWPE. For certain applications that require high fatigue resistance,such highly crosslinked UHMWPE (that is irradiated and melted) may notbe suitable; because, fatigue failure in the long term may compromisethe performance of the medical device. Therefore, there is a need toeither eliminate the residual free radicals or the oxidative effect ofresidual free radicals without melting. Such a method would preserve thecrystallinity of the irradiated UHMWPE and also preserve the mechanicalproperties and fatigue resistance.

It is generally known that mixing of polyethylene powder with anantioxidant prior to consolidation may improve the oxidation resistanceof the polyethylene material. Antioxidants, such as vitamin E andβ-carotene, have been mixed with UHMWPE powder or particles by severalinvestigators (see, Mori et al. p. 1017, Hand-out at the 47th AnnualMeeting, Orthopaedic Res Soc, Feb. 25-28, 2001, San Francisco, Calif.;McKellop et al. WO 01/80778; Schaffner et al. EP 0 995 450; Hahn D. U.S.Pat. No. 5,827,904; Lidgren et al. U.S. Pat. No. 6,448,315), in attemptsto improve wear resistance. Mori et al. also described that irradiationdoes not decrease the oxidation resistance of antioxidant-dopedpolyethylene. The investigators (see, McKellop et al. WO 01/80778;Schaffner et al. EP 0 995 450; Hahn D. U.S. Pat. No. 5,827,904; Lidgrenet al. U.S. Pat. No. 6,448,315) described mixing polyethylene powderwith antioxidants, followed by consolidating the antioxidant-powder mixto obtain oxidation resistant polyethylene. Mixing of the resin powder,flakes, or particles with vitamin E and consolidation thereafter resultin changes in color of polymeric material to yellow (see for example,U.S. Pat. No. 6,448,315). In addition, the addition of the antioxidantto the UHMWPE prior to irradiation can inhibit crosslinking of theUHMWPE during irradiation. However, crosslinking is needed to increasethe wear resistance of the polymer. Therefore, it would be preferable tohave a medical implant, or any polymeric component thereof, doped withan antioxidant and subsequent annealing in its consolidated solid form,such as feed-stock, machined components, or molded components.

SUMMARY OF THE INVENTION

The present invention relates generally to methods of making oxidationresistant medical devices that comprise one or more polymeric materials,as well as such materials made thereby. More specifically, the inventionrelates to methods of manufacturing antioxidant doped medical devicescontaining cross-linked polyethylene, for example, cross-linkedultra-high molecular weight polyethylene (UHMWPE), and materials usedtherein, as well as such materials made thereby. More specifically, theinvention relates to methods of manufacturing antioxidant-doped,non-oxidizing medical device containing cross-linked polyethylene withresidual free radicals, for example, irradiated ultra-high molecularweight polyethylene (UHMWPE) and materials used therein, and materialsmade thereby.

In one aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) providing consolidatedand cross-linked polymeric material that has been irradiated withionizing radiation; b) doping the consolidated and cross-linkedpolymeric material with an antioxidant by diffusion; and c) annealingthe antioxidant-doped cross-linked polymeric material in liquid orgaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure.Cross-linked polymeric materials obtainable by these methods also areprovided.

In another aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) providing consolidatedand cross-linked polymeric material that has been irradiated withionizing radiation; b) doping the consolidated and cross-linkedpolymeric material with an antioxidant by diffusion; c) annealing theantioxidant-doped cross-linked polymeric material in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; and d) heating theconsolidated and cross-linked polymeric material to a temperature belowthe melting point of the consolidated and cross-linked polymericmaterial. Cross-linked polymeric materials obtainable by these methodsalso are provided.

In another aspect, the invention provides methods of making cross-linkedpolymeric material, wherein the cross-linked polymeric material issoaked in a solution, of about 50% by weight, of an antioxidant in analcohol, such as ethanol, wherein the cross-linked polymeric material isdiffused with the antioxidant in a supercritical fluid, such as CO₂.Cross-linked polymeric materials obtainable by these methods also areprovided.

In another aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) placing a consolidatedand cross-linked polymeric material in a pressure chamber; b) fillingthe chamber with an antioxidant, either in a neat form (about 100%) orin a solution such as a 50% mixture of the antioxidant and alcohol, suchas ethanol; c) pressurizing the chamber to enhance diffusion of theantioxidant into the consolidated and cross-linked polymeric material;and d) annealing the antioxidant-doped cross-linked polymeric materialin liquid or gaseous environment and under various temperature andpressure conditions, for example, in boiling water under atmosphericpressure. Cross-linked polymeric materials obtainable by these methodsalso are provided.

In another aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) doping the consolidatedpolymeric material with an antioxidant by diffusion; and b) annealingthe antioxidant-doped polymeric material in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; c) irradiating theconsolidated polymeric material with ionizing radiation, thereby forminga consolidated and cross-linked polymeric material; and d) annealing theconsolidated and cross-linked polymeric material at a temperature belowor above melt of the consolidated and cross-linked polymeric material.Cross-linked polymeric materials obtainable by these methods also areprovided.

According to another aspect, the invention provides methods of makingcross-linked polymeric material, comprising the steps of: a)consolidating a polymeric material; b) irradiating the polymericmaterial with ionizing radiation, thereby forming a consolidated andcross-linked polymeric material; c) doping the consolidated andcross-linked polymeric material with an antioxidant by diffusion; d)annealing the antioxidant-doped cross-linked polymeric material inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure;and e) heating the consolidated and cross-linked polymeric material at atemperature below the melting point of the consolidated and cross-linkedpolymeric material. Cross-linked polymeric materials obtainable by thesemethods also are provided.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) irradiating the consolidated polymericmaterial with ionizing radiation, thereby forming a consolidated andcross-linked polymeric material; d) machining the consolidated andcross-linked polymeric material, thereby forming a medical implant; e)doping the medical implant with an antioxidant by diffusion, therebyforming an antioxidant-doped cross-linked medical implant; and f)annealing the antioxidant-doped cross-linked medical implant in liquidor gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure.Medical implants obtainable by these methods also are provided.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a consolidated polymeric material; b)irradiating the consolidated polymeric material with ionizing radiation,thereby forming a consolidated and cross-linked polymeric material; c)machining the consolidated and cross-linked polymeric material, therebyforming a medical implant; d) doping the medical implant with anantioxidant by diffusion, thereby forming an antioxidant-dopedcross-linked medical implant; and e) annealing the antioxidant-dopedcross-linked medical implant in liquid or gaseous environment and undervarious temperature and pressure conditions, for example, in boilingwater under atmospheric pressure. Medical implants obtainable by thesemethods also are provided.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant-doped cross-linked polymeric materialcomprising: a) irradiating a consolidated polymeric material withionizing radiation, thereby forming a cross-linked polymeric material;b) machining the consolidated and cross-linked polymeric material,thereby forming a medical implant; c) doping the medical implant with anantioxidant by diffusion; and d) annealing the antioxidant-dopedcross-linked medical implant in liquid or gaseous environment and undervarious temperature and pressure conditions, for example, in boilingwater under atmospheric pressure. Medical implants obtainable by thesemethods also are provided.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant-doped cross-linked polymeric materialcomprising: a) machining a consolidated polymeric material, therebyforming a medical implant; b) doping the medical implant with anantioxidant by diffusion; c) annealing the antioxidant-doped medicalimplant in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure; and d) irradiating the medical implant, thereby forming amedical implant containing cross-linked polymeric material. Medicalimplants obtainable by these methods also are provided.

In another aspect, the invention provides methods of making a medicalimplant containing polymeric material comprising: a) irradiating thepolymeric material with ionizing radiation, thereby forming across-linked polymeric material; b) doping the cross-linked polymericmaterial with an antioxidant by diffusion, wherein the cross-linkedpolymeric material is annealed at a temperature below the melt or abovethe melt of the consolidated and cross-linked polymeric material; and c)annealing the antioxidant-doped cross-linked polymeric material inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure.Medical implants obtainable by these methods also are provided.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)compression molding of polymeric material to another piece, therebyforming an interface and an interlocked hybrid material; b) irradiatingthe interlocked hybrid material by ionizing radiation, thereby forming across-linked and interlocked hybrid material; c) doping the cross-linkedand interlocked hybrid material with an antioxidant by diffusion; and d)annealing the antioxidant-doped cross-linked interlocked hybrid inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure.Medical implants containing cross-linked polymeric materials that areobtainable by these methods also are provided.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)compression molding of polymeric material to another piece, therebyforming an interface and an interlocked hybrid material; b) doping theinterlocked hybrid material with an antioxidant by diffusion; c)annealing the antioxidant-doped interlocked hybrid in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; and d) irradiatingthe interlocked hybrid material by ionizing radiation, thereby forming across-linked and interlocked hybrid material. Medical implantscontaining cross-linked polymeric materials that are obtainable by thesemethods also are provided.

In another aspect, the invention provides methods of making a sterilemedical implant containing cross-linked polymeric material comprising:a) direct compression molding a polymeric material, thereby forming amedical implant; b) irradiating the medical implant to crosslink thepolymeric material; c) doping the irradiated medical implant with anantioxidant by diffusion; d) annealing the antioxidant-dopedcross-linked medical implant in liquid or gaseous environment and undervarious temperature and pressure conditions, for example, in boilingwater under atmospheric pressure; e) packaging the irradiated andantioxidant-doped medical implant; and f) sterilizing the packagedirradiated and antioxidant-doped medical implant by ionizing radiationor gas sterilization, thereby forming a cross-linked and sterile medicalimplant. Medical implants containing cross-linked polymeric materialsthat are obtainable by these methods also are provided.

In another aspect, the invention provides methods of making a sterilemedical implant containing antioxidant doped cross-linked polymericmaterial comprising: a) machining a consolidated polymeric material,thereby forming a medical implant; b) irradiating the medical implant,thereby forming a medical implant containing cross-linked polymericmaterial; c) doping the medical implant with an antioxidant bydiffusion; d) annealing the antioxidant-doped cross-linked medicalimplant in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure; e) packaging the irradiated and antioxidant-doped medicalimplant; and f) sterilizing the packaged medical implant by ionizingradiation or gas sterilization, thereby forming a cross-linked andsterile medical implant. Medical implants obtainable by these methodsalso are provided.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) dopinga polymeric material with an antioxidant by diffusion; b) annealing theantioxidant-doped polymeric material in liquid or gaseous environmentand under various temperature and pressure conditions, for example, inboiling water under atmospheric pressure; c) compression molding of thepolymeric material to another piece, thereby forming an interface and aninterlocked hybrid material; and d) irradiating the interlocked hybridmaterial by ionizing radiation, thereby forming a cross-linked andinterlocked hybrid material. Medical implants containing cross-linkedpolymeric materials that are obtainable by these methods also areprovided.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) directcompression molding of the polymeric material, thereby forming a medicalimplant; b) irradiating the medical implant by ionizing radiation,thereby forming a consolidated and cross-linked medical implant; c)doping the consolidated and cross-linked medical implant with anantioxidant by diffusion; and d) annealing the antioxidant-dopedcross-linked medical implant in liquid or gaseous environment and undervarious temperature and pressure conditions, for example, in boilingwater under atmospheric pressure. Medical implants containingcross-linked polymeric materials that are obtainable by these methodsalso are provided.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant-doped cross-linked polymeric materialcomprising: a) machining a consolidated polymeric material, therebyforming a medical implant; b) irradiating the medical implant, therebyforming a medical implant containing cross-linked polymeric material; c)doping the medical implant with an antioxidant by diffusion; and d)annealing the antioxidant-doped cross-linked medical implant in liquidor gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure.Medical implants containing antioxidant-doped cross-linked polymericmaterials that are obtainable by these methods also are provided.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) directcompression molding polymeric material, thereby forming a medicalimplant; b) doping the medical implant with an antioxidant by diffusion;c) annealing the antioxidant-doped medical implant in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; d) packaging themedical implant; and e) irradiating the packaged medical implant byionizing radiation, thereby forming a consolidated and cross-linked andsterile medical implant. Medical implants containing cross-linkedpolymeric materials that are obtainable by these methods also areprovided.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)machining a consolidated polymeric material, thereby forming a medicalimplant; b) doping the medical implant with an antioxidant by diffusion;c) annealing the antioxidant-doped medical implant in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; d) packaging themedical implant; and e) irradiating the packaged medical implant byionizing radiation, thereby forming a consolidated and cross-linked andsterile medical implant. Medical implants containing cross-linkedpolymeric materials that are obtainable by these methods also areprovided.

In another aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) placing a consolidatedand cross-linked polymeric material in a pressure chamber; b) fillingthe chamber with an antioxidant; c) pressurizing the chamber to enhancediffusion of the antioxidant into the consolidated and cross-linkedpolymeric material; and d) annealing the antioxidant-doped cross-linkedpolymeric material in liquid or gaseous environment and under varioustemperature and pressure conditions, for example, in boiling water underatmospheric pressure. Medical implants containing antioxidant-dopedcross-linked polymeric materials that are obtainable by these methodsalso are provided.

In another aspect, the invention provides methods of making medicaldevices containing cross-linked polymeric material comprising: a)irradiating a manufactured medical device consisting of consolidatedpolymeric material with ionizing radiation, thereby forming aconsolidated and cross-linked polymeric material; b) doping theconsolidated and cross-linked polymeric material with an antioxidant bydiffusion, thereby forming an antioxidant-doped consolidated andcross-linked polymeric material; and c) annealing the antioxidant-dopedcross-linked polymeric material in liquid or gaseous environment andunder various temperature and pressure conditions, for example, inboiling water under atmospheric pressure. Medical devices containingcross-linked polymeric materials that are obtainable by these methodsalso are provided.

In another aspect, the invention provides methods of making a packagingfor medical devices that is resistant to oxidation, when subjected toeither sterilization or crosslinking doses of ionizing radiation,comprising: a) doping the packaging material with an antioxidant bydiffusion; b) annealing the antioxidant-doped packaging material inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure; c)inserting a medical device in the packaging material; d) sealing thepackaging material containing the medical device, thereby forming apackaged medical device; and d) irradiating the packaged medical devicewith ionizing radiation or gas sterilization. Medical devices obtainableby these methods also are provided.

In another aspect, the invention provides methods of making a packagingfor pharmaceutical compounds that is resistant to oxidation, whensubjected to either sterilization or crosslinking doses of ionizingradiation, comprising: a) doping the packaging material with anantioxidant by diffusion; b) annealing the antioxidant-doped packagingmaterial in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure; c) inserting a pharmaceutical compound in the packagingmaterial; d) sealing the packaging material containing thepharmaceutical compound, thereby forming a packaged pharmaceuticalcompound; and e) irradiating the packaged pharmaceutical compound withionizing radiation or gas sterilization. Packaging materials obtainableby these methods also are provided.

Yet in another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material, wherein theimplant comprises medical devices, including acetabular liner, shoulderglenoid, patellar component, finger joint component, ankle jointcomponent, elbow joint component, wrist joint component, toe jointcomponent, bipolar hip replacements, tibial knee insert, tibial kneeinserts with reinforcing metallic and polyethylene posts, intervertebraldiscs, heart valves, tendons, stents, and vascular grafts, wherein thepolymeric material is polymeric resin powder, polymeric flakes,polymeric particles, or the like, or a mixture thereof. Medical implantscontaining cross-linked polymeric materials that are obtainable by thesemethods also are provided.

Yet in another aspect, the invention provides methods of making medicalimplants, including non-permanent implants, containing cross-linkedpolymeric material, wherein the implant comprises medical device,including balloon catheters, sutures, tubing, and intravenous tubing,wherein the polymeric material is polymeric resin powder, polymericflakes, polymeric particles, or the like, or a mixture thereof. Asdescribed herein, the polymeric balloons, for example, polyether-blockco-polyamide polymer (PeBAX®), Nylon, and polyethylene terephthalate(PET) balloons are doped with vitamin E and irradiated before, during,or after doping. Medical implants obtainable by these methods also areprovided.

Yet in another aspect, the invention provides methods of making apackaging for a medical device, wherein the packaging is resistant tooxidation when subjected to sterilization with ionizing radiation or gassterilization. The packaging include barrier materials, for example,blow-molded blister packs, heat-shrinkable packaging, thermally-sealedpackaging, or the like or a mixture thereof. Packaging materials for amedical devices obtainable by these methods also are provided.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) dopingthe consolidated polymeric material with an antioxidant by diffusion; b)annealing the antioxidant-doped polymeric material in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; and c) irradiatingthe polymeric material with ionizing radiation, thereby forming aconsolidated and cross-linked polymeric material. Medical implantscontaining cross-linked polymeric materials obtainable by these methodsalso are provided.

In one aspect, antioxidant-doped medical implants are packaged andsterilized by ionizing radiation or gas sterilization to obtain sterileand cross-linked medical implants.

In another aspect, the polymeric material of the instant invention is apolymeric resin powder, polymeric flakes, polymeric particles, or thelike, or a mixture thereof, wherein the irradiation can be carried outin an atmosphere containing between about 1% and about 22% oxygen,wherein the radiation dose is between about 25 kGy and about 1000 kGy.

In another aspect, the polymeric material of the instant invention ispolymeric resin powder, polymeric flakes, polymeric particles, or thelike, or a mixture thereof, wherein the polymeric material is irradiatedafter consolidation in an inert atmosphere containing a gas, forexample, nitrogen, argon, helium, neon, or the like, or a combinationthereof, wherein the radiation dose is between about 25 kGy and about1000 kGy.

In another aspect, the polymeric material of the instant invention isconsolidated polymeric material, where the consolidation can be carriedout by compression molding to form a slab from which a medical device ismachined.

In another aspect, the polymeric material of the instant invention isconsolidated polymeric material, where the consolidation can be carriedout by direct compression molding to form a finished medical device.

Yet in another aspect, the polymeric material of the instant inventionis consolidated polymeric material, where the consolidation can becarried out by compression molding to another piece to form an interfaceand an interlocked hybrid material.

Still in another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprising:a) compression molding of polymeric material to another piece, therebyforming an interface and an interlocked hybrid material; b) irradiatingthe interlocked hybrid material by ionizing radiation, thereby forming across-linked and interlocked hybrid material; c) doping the cross-linkedand interlocked hybrid material with an antioxidant by diffusion; and d)annealing the antioxidant-doped cross-linked and interlocked hybridmaterial in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure. Medical implants containing cross-linked polymeric materialsthat are obtainable by these methods also are provided.

According to one aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprisingcompression molding of polymeric material to another piece, such as ametallic or a non metallic piece, for example, a metal, a ceramic, or apolymer, thereby forming an interface and an interlocked hybridmaterial, wherein the interface is a metal-polymer or a metal-ceramicinterface.

Yet according to another aspect, the invention provides methods ofmaking a medical implant containing cross-linked polymeric materialcomprising: a) compression molding of polymeric material to anotherpiece, thereby forming an interface and an interlocked hybrid material;b) annealing the antioxidant-doped interlocked hybrid material in liquidor gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure; c)doping the interlocked hybrid material with an antioxidant, for example,an α-tocopherol, such as vitamin E, by diffusion; and d) irradiating theinterlocked hybrid material by ionizing radiation, thereby forming across-linked and interlocked hybrid material. Medical implantscontaining cross-linked polymeric materials that are obtainable by thesemethods also are provided.

Another aspect of the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)compression molding a polymeric material, thereby forming a medicalimplant; b) irradiating the medical implant to crosslink the polymericmaterial; c) annealing the antioxidant-doped cross-linked medicalimplant in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure; d) doping the irradiated medical implant with an antioxidantby diffusion; e) packaging the irradiated and antioxidant-doped medicalimplant; and f) sterilizing the packaged irradiated andantioxidant-doped medical implant by ionizing radiation or gassterilization, thereby forming a cross-linked and sterile medicalimplant. Medical implants obtainable by these methods also are provided.

Yet in another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprising:a) machining a consolidated polymeric material, thereby forming amedical implant; b) irradiating the medical implant to crosslink thepolymeric material; c) doping the irradiated medical implant with anantioxidant by diffusion; d) annealing the antioxidant-dopedcross-linked medical implant in liquid or gaseous environment and undervarious temperature and pressure conditions, for example, in boilingwater under atmospheric pressure; e) packaging the irradiated andantioxidant-doped medical implant; and f) sterilizing the packagedirradiated and antioxidant-doped medical implant by ionizing radiationor gas sterilization, thereby forming a cross-linked and sterile medicalimplant. Medical implants obtainable by these methods also are provided.

According to another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprising:a) compression molding of polymeric material to another piece, therebyforming an interface and an interlocked hybrid material; b) doping theinterlocked hybrid material with an antioxidant by diffusion; c)annealing the antioxidant-doped interlocked hybrid material in liquid orgaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure;and d) irradiating the interlocked hybrid material by ionizingradiation, thereby forming a cross-linked and interlocked hybridmaterial. Medical implants containing cross-linked polymeric materialobtainable by these methods also are provided.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) directcompression molding of the polymeric material, thereby forming a medicalimplant; b) irradiating the medical implant by ionizing radiation,thereby forming a consolidated and cross-linked medical implant; c)doping the consolidated and cross-linked medical implant with anantioxidant by diffusion; and d) annealing the antioxidant-dopedcross-linked medical implant in liquid or gaseous environment and undervarious temperature and pressure conditions, for example, in boilingwater under atmospheric pressure. Medical implants containingcross-linked polymeric materials obtainable by these methods also areprovided.

Yet in another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprising:a) machining a consolidated polymeric material, thereby forming amedical implant; b) irradiating the medical implant by ionizingradiation, thereby forming a consolidated and cross-linked medicalimplant; c) doping the consolidated and cross-linked medical implant anantioxidant by diffusion; and d) annealing the antioxidant-dopedcross-linked medical implant in liquid or gaseous environment and undervarious temperature and pressure conditions, for example, in boilingwater under atmospheric pressure. Medical implants obtainable by thesemethods also are provided.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) doping the consolidated polymeric materialwith an antioxidant by diffusion; d) annealing the antioxidant-dopedpolymeric material in liquid or gaseous environment and under varioustemperature and pressure conditions, for example, in boiling water underatmospheric pressure; e) irradiating the antioxidant doped polymericmaterial by ionizing radiation, thereby forming an antioxidant dopedcross-linked polymeric material; and f) machining the cross-linkedpolymeric material, thereby forming an antioxidant doped cross-linkedmedical implant. Medical implants obtainable by these methods also areprovided.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a consolidated polymeric material; b)doping the consolidated polymeric material with an antioxidant bydiffusion; c) annealing the antioxidant-doped polymeric material inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure; d)irradiating the antioxidant doped polymeric material by ionizingradiation, thereby forming an antioxidant doped cross-linked polymericmaterial; and e) machining the cross-linked polymeric material, therebyforming an antioxidant doped cross-linked medical implant. Medicalimplants obtainable by these methods also are provided.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) doping the consolidated polymeric materialwith an antioxidant by diffusion; d) annealing the antioxidant-dopedpolymeric material in liquid or gaseous environment and under varioustemperature and pressure conditions, for example, in boiling water underatmospheric pressure; e) machining the antioxidant doped polymericmaterial, thereby forming an antioxidant doped polymeric material; andf) irradiating the antioxidant doped cross-linked polymeric material byionizing radiation, thereby forming an antioxidant doped cross-linkedmedical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a consolidated polymeric material; b)doping the consolidated polymeric material with an antioxidant bydiffusion; c) annealing the antioxidant-doped polymeric material inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure; d)machining the antioxidant doped polymeric material, thereby forming anantioxidant doped polymeric material; and e) irradiating the antioxidantdoped cross-linked polymeric material by ionizing radiation, therebyforming an antioxidant doped cross-linked medical implant.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) directcompression molding polymeric material, thereby forming a medicalimplant; b) doping the medical implant an antioxidant by diffusion; c)packaging the medical implant; d) annealing the antioxidant-dopedmedical implant in liquid or gaseous environment and under varioustemperature and pressure conditions, for example, in boiling water underatmospheric pressure; and e) irradiating the packaged medical implant byionizing radiation, thereby forming a consolidated and cross-linked andsterile medical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) machining the consolidated polymericmaterial, thereby forming a medical implant; d) doping the medicalimplant with an antioxidant by diffusion, thereby forming anantioxidant-doped medical implant; e) annealing the antioxidant-dopedmedical implant in liquid or gaseous environment and under varioustemperature and pressure conditions, for example, in boiling water underatmospheric pressure; f) packaging the medical implant; and g)irradiating the packaged medical implant by ionizing radiation, therebyforming an antioxidant doped cross-linked and sterile medical implant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) machining the consolidated polymeric material, therebyforming a medical implant; c) doping the medical implant with anantioxidant by diffusion, thereby forming an antioxidant doped medicalimplant; d) annealing the antioxidant-doped medical implant in liquid orgaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure; e)packaging the medical implant; and f) irradiating the packaged medicalimplant by ionizing radiation, thereby forming an antioxidant dopedcross-linked and sterile medical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) doping the consolidated polymeric materialwith an antioxidant by diffusion, thereby forming an antioxidant dopedpolymeric material; d) annealing the antioxidant-doped polymericmaterial in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure; e) machining the antioxidant-doped polymeric material, therebyforming a medical implant; f) packaging the medical implant; and g)irradiating the packaged medical implant by ionizing radiation, therebyforming an antioxidant doped cross-linked and sterile medical implant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) doping the consolidated polymeric material with anantioxidant by diffusion, thereby forming an antioxidant-doped polymericmaterial; c) annealing the antioxidant-doped polymeric material inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure; d)machining the antioxidant-doped polymeric material, thereby forming amedical implant; e) packaging the medical implant; and f) irradiatingthe packaged medical implant by ionizing radiation, thereby forming anantioxidant doped cross-linked and sterile medical implant.

In another aspect, the invention provides methods of making a sterilemedical implant containing antioxidant doped cross-linked polymericmaterial comprising: a) irradiating a consolidated polymeric material,thereby forming a cross-linked polymeric material; b) machining theconsolidated and cross-linked polymeric material, thereby forming amedical implant; c) doping the medical implant with an antioxidant bydiffusion; d) annealing the antioxidant-doped cross-linked medicalimplant in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure; e) packaging the irradiated and antioxidant-doped medicalimplant; and f) sterilizing the packaged medical implant by ionizingradiation or gas sterilization, thereby forming a cross-linked andsterile medical implant.

In another aspect, the invention provides methods of making a sterilemedical implant containing antioxidant doped cross-linked polymericmaterial comprising: a) doping a polymeric material with an antioxidant;b) annealing the antioxidant-doped polymeric material in liquid orgaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure; c)consolidating the antioxidant-doped polymeric material; d) machining theconsolidated antioxidant-doped polymeric material, thereby forming anantioxidant-doped medical implant; e) irradiating the medical implant,thereby forming a medical implant containing antioxidant-dopedcross-linked polymeric material; f) packaging the antioxidant-dopedcross-linked medical implant; and g) sterilizing the packaged medicalimplant by ionizing radiation or gas sterilization, thereby forming across-linked and sterile medical implant.

In another aspect, the invention provides methods of making a sterilemedical implant containing antioxidant doped cross-linked polymericmaterial comprising: a) doping a polymeric material with an antioxidant;b) annealing the antioxidant-doped polymeric material in liquid orgaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure; c)consolidating the antioxidant-doped polymeric material; d) irradiatingthe consolidated polymeric material, thereby forming anantioxidant-doped cross-linked polymeric material; e) machining theconsolidated and cross-linked polymeric material, thereby forming amedical implant containing an antioxidant-doped cross-linked polymericmaterial; f) packaging the antioxidant-doped cross-linked medicalimplant; and g) sterilizing the packaged medical implant by ionizingradiation or gas sterilization, thereby forming a cross-linked andsterile medical implant.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) dopinga polymeric material with an antioxidant by diffusion; b) annealing theantioxidant-doped polymeric material in liquid or gaseous environmentand under various temperature and pressure conditions, for example, inboiling water under atmospheric pressure; c) irradiating theantioxidant-doped polymeric material by ionizing radiation, therebyforming a cross-linked antioxidant-doped polymeric material; and d)compression molding of the cross-linked antioxidant-doped polymericmaterial to another piece, thereby forming a cross-linked andinterlocked hybrid material.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)irradiating a consolidated polymeric material by ionizing radiation,thereby forming a consolidated and cross-linked polymeric material; b)direct compression molding of the polymeric material, thereby forming aconsolidated and cross-linked medical implant; c) doping theconsolidated and cross-linked medical implant with an antioxidant bydiffusion; and d) annealing the antioxidant-doped cross-linked medicalimplant in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant doped cross-linked polymeric materialcomprising: a) doping a polymeric material with an antioxidant; b)annealing the antioxidant-doped polymeric material in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; c) consolidatingthe antioxidant-doped polymeric material; d) machining the consolidatedantioxidant-doped polymeric material, thereby forming anantioxidant-doped medical implant; and e) irradiating the medicalimplant, thereby forming a medical implant containing antioxidant-dopedcross-linked polymeric material.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant doped cross-linked polymeric materialcomprising: a) doping a polymeric material with an antioxidant; b)annealing the antioxidant-doped polymeric material in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; c) consolidatingthe antioxidant-doped polymeric material; d) irradiating theconsolidated polymeric material, thereby forming an antioxidant-dopedcross-linked polymeric material; and e) machining the consolidated andcross-linked polymeric material, thereby forming a medical implantcontaining an antioxidant-doped cross-linked polymeric material. Medicalimplants containing cross-linked polymeric materials that are obtainableby the above methods also are provided.

Yet in another aspect, the invention provides methods of making anon-permanent medical device containing cross-linked polymeric materialcomprising: a) doping a manufactured medical device containingconsolidated polymeric material with an antioxidant by diffusion,thereby forming an antioxidant-doped polymeric material; and b)annealing the antioxidant-doped polymeric material in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; c) irradiating themedical device with ionizing radiation, thereby forming a cross-linkedpolymeric material.

In another aspect, the invention provides non-oxidizing cross-linkedpolymeric materials with detectable residual free radicals.

In another aspect, the invention provides non-oxidizing cross-linkedmedical implants, including permanent and non-permanent medical devices,with detectable residual free radicals.

In another aspect, the invention provides non-oxidizing cross-linkedmedical implants, including permanent and non-permanent medical devices,with detectable residual free radicals and with a gradient ofantioxidant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) machining the consolidated polymericmaterial, thereby forming a medical implant; d) irradiating the medicalimplant with ionizing radiation, thereby forming a cross-linked medicalimplant; e) doping the medical implant with an antioxidant by diffusion,thereby forming an antioxidant-doped cross-linked medical implant; andf) annealing the antioxidant-doped cross-linked medical implant inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) machining the consolidated polymeric material, therebyforming a medical implant; c) irradiating the medical implant withionizing radiation, thereby forming an antioxidant-doped cross-linkedmedical implant; d) doping the medical implant with an antioxidant bydiffusion, thereby forming an antioxidant-doped cross-linked medicalimplant; and e) annealing the antioxidant-doped cross-linked medicalimplant in liquid or gaseous environment and under various temperatureand pressure conditions, for example, in boiling water under atmosphericpressure.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) machining the consolidated polymericmaterial, thereby forming a medical implant; d) doping the medicalimplant with an antioxidant by diffusion, thereby forming anantioxidant-doped medical implant; e) annealing the antioxidant-dopedmedical implant in liquid or gaseous environment and under varioustemperature and pressure conditions, for example, in boiling water underatmospheric pressure; and f) irradiating the medical implant withionizing radiation, thereby forming an antioxidant-doped cross-linkedmedical implant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) machining the consolidated polymeric material, therebyforming a medical implant; c) doping the medical implant with anantioxidant by diffusion, thereby forming an antioxidant-doped medicalimplant; d) annealing the antioxidant-doped medical implant in liquid orgaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure;and e) irradiating the medical implant with ionizing radiation, therebyforming an antioxidant-doped cross-linked medical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) irradiating the polymeric material withionizing radiation, thereby forming a cross-linked polymeric material;d) doping the polymeric material with an antioxidant by diffusion,thereby forming an antioxidant-doped cross-linked polymeric material; e)annealing the antioxidant-doped cross-linked polymeric material inliquid or gaseous environment and under various temperature and pressureconditions, for example, in boiling water under atmospheric pressure;and f) machining the polymeric material, thereby forming anantioxidant-doped cross-linked medical implant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) irradiating the polymeric material with ionizing radiation,thereby forming a cross-linked polymeric material; c) doping thepolymeric material with an antioxidant by diffusion, thereby forming anantioxidant-doped cross-linked polymeric material; d) annealing theantioxidant-doped cross-linked polymeric material in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; and e) machiningthe polymeric material, thereby forming an antioxidant-dopedcross-linked medical implant.

Another aspect of the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) compressionmolding the polymeric material, thereby forming a medical implant; c)doping the medical implant containing an interface or an interlockedhybrid material with an antioxidant by diffusion, thereby forming anantioxidant-doped medical implant; d) annealing the antioxidant-dopedmedical implant in liquid or gaseous environment and under varioustemperature and pressure conditions, for example, in boiling water underatmospheric pressure; e) packaging the medical implant; and f)irradiating the packaged medical implant by ionizing radiation, therebyforming an antioxidant-doped cross-linked and sterile medical implant.In another aspect, the polymeric material is compression molded toanother piece or a medical implant, thereby form an interface or aninterlocked hybrid material.

Another aspect of the invention provides methods of making a medicalimplant comprising: a) providing a compression molded polymeric materialforming a medical implant; b) doping the medical implant containing aninterface or an interlocked hybrid material with an antioxidant bydiffusion, thereby forming an antioxidant-doped medical implant; c)annealing the antioxidant-doped medical implant in liquid or gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure; d) packaging themedical implant; and e) irradiating the packaged medical implant byionizing radiation, thereby forming an antioxidant-doped cross-linkedand sterile medical implant. In another aspect, the polymeric materialis compression molded to another piece or a medical implant, therebyform an interface or an interlocked hybrid material.

Medical implants containing cross-linked polymeric materials that areobtainable by the all of the above methods also are provided.

Another aspect of the invention provides methods to increase theuniformity of an antioxidant in a doped polymeric material by annealingthe doped polymeric material below the melting point of the dopedpolymeric material, for example, annealing in a liquid or a gaseousenvironment and under various temperature and pressure conditions, forexample, in boiling water under atmospheric pressure or under pressurein order to anneal at a temperature above 100° C. and below the meltingpoint of the polymeric material. In another aspect, doping or annealingof polymeric materials prior to machining can be carried out at atemperature above the melting point of the polymeric material, forexample, at 150° C., 160° C., 170° C., 180° C., or higher.

Another aspect of the invention provides methods to increase theuniformity of an antioxidant in a doped polymeric material by annealingthe doped polymeric material above the melting point of the dopedpolymeric material.

According to another aspect of the invention, the annealing ofantioxidant-doped-polymeric material, -cross-linked polymeric material,or -medical implants, as described above, also can be carried out in afluid, for example, water or mineral oil, under pressure at atemperature below or above 100° C. and below the melting point of thepolymeric material.

According to another aspect of the invention, the doping of medicalimplant or polymeric material or cross-linked polymeric material with anantioxidant, as described herein, can be carried out in anantioxidant-emulsion, antioxidant-solution such as antioxidant-NaClsolution, or -mixture.

According to another aspect of the invention, the annealing ofantioxidant-doped-polymeric material, -cross-linked polymeric material,or -medical implants, as described above, also can be carried out inantioxidant-emulsion, antioxidant-solution such as antioxidant-NaClsolution, or -mixture, under atmospheric pressure or under pressure at atemperature below or above 100° C. and below the melting point of thepolymeric material and for a time period between about 1 minute andabout 30 days. In another aspect, annealing ofantioxidant-doped-polymeric materials or antioxidant-doped-cross-linkedpolymeric materials prior to machining can be carried out at atemperature above the melting point of the polymeric material, forexample, at 150° C., 160° C., 170° C., 180° C., or higher.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows penetration depth of vitamin E diffusion into UHMWPE atroom temperature, 100° C., 120° C. and 130° C.

FIG. 2 shows the oxidation index profile as a function of depth into oneof the representative aged cubes of seven groups studied (Group TCRT,Group RT1, Group RT16, Group TC100C16, Group 100C1, Group TC100C1, andGroup 100C16). All cubes were fabricated from an irradiated polyethyleneand four of which were doped with vitamin E under various conditions.Thermal control cubes were not treated with vitamin E. Vitamin E dopedcubes show less oxidation at the surface and in the bulk of the samplesthan their corresponding thermal controls.

FIG. 3 shows the diffusion profiles for vitamin E through unirradiatedUHMWPE doped at 130° C. for 96 hours as a function of subsequentannealing time at 130° C.

FIG. 4 schematically shows examples of sequences of processing UHMWPEand doping at various steps.

FIG. 5 schematically shows examples of sequences of processing UHMWPEand doping at various steps.

FIGS. 6A and B show depth-profiles of sensitive vitamin E index(sensVitE) for vitamin E doped UHMWPE cubes. FIG. 6A shows vitamin Eprofiles obtained in vitamin E doped cubes that were machined from a 100kGy irradiated UHMWPE (solid marks) and the vitamin E profiles of thedoped cubes after annealing in boiling water (hollow marks). FIG. 6Bshows the vitamin E penetration profiles at a higher resolution.

FIGS. 7A and B show depth-profiles of sensitive vitamin E index(sensVitE) for vitamin E doped and vitamin E-water mixture doped UHMWPEcubes. FIG. 7A depicts vitamin E profiles obtained from the 24 hourdoped cubes. FIG. 7B shows the sensVitE profiles of cubes doped forvarious time period at 100° C.

FIG. 8 shows depth-profiles of sensitive vitamin E index (sensVitE) forvitamin E doped UHMWPE cubes and the sensVitE of UHMWPE cubes that weresubjected to post-doping-annealing in boiling water and boiling NaClsolution for 24 hours.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods of making oxidation resistantmedical implants that comprise medical devices, including permanent andnon-permanent devices, and packaging that comprises polymeric material,such as polyethylene. The invention pertains to methods of dopingconsolidated polyethylene, such as UHMWPE, with antioxidants, before,during, or after crosslinking the consolidated polyethylene, andsubsequent annealing in a liquid or a gaseous environment under varioustemperature and pressure conditions.

In one aspect of the invention, the doping of consolidated polyethylenecan be carried out by diffusion of an antioxidant, for example,α-tocopherol, such as vitamin E. According to one aspect of theinvention, the diffusion of the antioxidant is accelerated by increasingthe temperature and/or pressure.

In another aspect, antioxidant doped consolidated polyethylene issubsequently annealed in a liquid or a gaseous environment and undervarious temperature and pressure conditions.

According to another aspect of the invention, an antioxidant isdelivered in various forms, including in a pure form, for example, aspure vitamin E, or dissolved in a solvent.

According to another aspect of the invention, diffusion rate of anantioxidant into the polyethylene is increased by increasing theconcentration of the antioxidant solution, for example, a vitamin Esolution.

In accordance with another aspect of the invention, diffusion rate of anantioxidant into the polyethylene is increased by swelling theconsolidated polyethylene in a supercritical fluid, for example, in asupercritical CO₂, i.e., the temperature being above the supercriticaltemperature, which is 31.3° C., and the pressure being above thesupercritical pressure, which is 73.8 bar.

In general, for example, in case of vitamin E, as the antioxidant,mixing the resin powder, flakes, particles, or a mixture thereof, withvitamin E and consolidation thereafter result in changes in color ofpolymeric material to yellow. According to the instant invention, dopingsubsequent to consolidation avoids the exposure of vitamin E to hightemperatures and pressures of consolidation and prevents thediscoloration of the polymeric material. The invention also decreasesthe thermal effects on the antioxidant. The thermal effects can reducethe effectiveness of the antioxidant in protecting the polymericmaterial against oxidation.

Doping in the consolidated state also allows one to achieve a gradientof antioxidant in consolidated polymeric material. One can dope acertain thickness surface layer where the oxidation of the polymericmaterial in a medical device is of concern in terms of wear. This can beachieved by simply dipping or soaking finished devices, for example, afinished medical implant, for example, in pure vitamin E or in asolution of vitamin E or an emulsion of vitamin E at a given temperatureand for a given amount of time.

Doping after crosslinking can result in an elevated antioxidantconcentration near the surface and can increase the oxidative stabilityof the surface and near surface polyethylene in case of the diffusion ofthe antioxidant out of polyethylene. Generally, the antioxidant (forexample, vitamin E) diffuses out of the polyethylene either during shelfstorage and/or during in vivo use, which results in a surface regiondepleted from the antioxidant, and therefore the surface becomes lessoxidation resistant. If polyethylene powder is blended with antioxidantbefore consolidation, the amount of the antioxidant can be increased toprevent surface depletion. However, higher concentrations of antioxidantin the blend would decrease the level of crosslink density and thusincrease wear rates. According to the invention, the surfaceconcentration of the antioxidant can be tailored to be higher than thebulk. Therefore, even with diffusion of the antioxidant out of thepolyethylene, there will be no substantial depletion of the antioxidantand oxidation resistance will be maintained.

The emulsion of vitamin E can be a mixture of water and vitamin E and/ordi-methyl sulfoxide (DMSO) and vitamin-E, mineral oil, or any otherhydrophilic fluid and vitamin E. The emulsion can be maintained bystirring. The doping in the emulsion can be carried out at anytemperature for any amount of time, both can be varied to achieve acertain penetration level of vitamin E into the UHMWPE sample orimplant. The concentration of vitamin E in the emulsion can vary betweenabout 1% (by volume) and 99% (by volume). Preferably, 30% (by volume)vitamin E can be used. The emulsion also can be formed by adding vitaminE into a mixture of hydrophilic fluids, such as a mixture of waterand/or DMSO. The emulsion also can be formed by adding a solution ofvitamin E, such as vitamin E/ethanol mixture into a hydrophilic fluid ora mixture of hydrophilic fluid. The solution of vitamin E used also canbe made by a mixture of solvents. The emulsion also can be prepared byheating the components of the emulsion separately and mixing the heatedcomponents together, for example, an emulsion can be prepared by heatingwater to about 100° C. and heating the vitamin E to about 100° C., andthen by mixing the two heated materials together.

According to the methods described herein, an antioxidant, for example,vitamin E, can be doped into the polymeric material either before,during, or after irradiation (See for example, FIGS. 4 and 5).

It may be possible that the doped antioxidant can leach out of thepolymeric material used in fabrication of medical implants or medicaldevices either during storage prior to use or during in vivo service.For a permanent medical device, the in vivo duration can be as long asthe remaining life of the patient, which is the length of time betweenimplantation of the device and the death of the patient, for example,1-120 years, typically 5-30 years. If leaching out of the antioxidant isan issue, the irradiation of the medical implant or medical device orirradiation of any portion thereof can be carried out after doping theantioxidant. This can ensure crosslinking of the antioxidant to the hostpolymer through covalent bonds and thereby prevent loss of antioxidantfrom the medical implant or the device. Alternatively, the surfaceconcentration of the antioxidant can be kept high enough that anyleeching out of the antioxidant will not adversely affect oxidationresistance and/or other desired properties of the polyethylene impartedby the presence of the anti-oxidant. In one aspect of the invention, theimplant can be doped a second time after the annealing step to increasethe surface concentration level of the antioxidant.

According to another aspect of the invention, polymeric material, forexample, resin powder, flakes, particles, or a mixture thereof, is mixedwith an antioxidant and then the mixture is consolidated. Theconsolidated antioxidant doped polymeric material can be machined to useas a component in a medical implant or as a medical device.

According to another aspect of the invention, consolidated polymericmaterial, for example, consolidated resin powder, molded sheet, blownfilms, tubes, balloons, flakes, particles, or a mixture thereof, can bedoped with an antioxidant, for example, vitamin E in the form ofα-Tocopherol, by diffusion. Consolidated polymeric material, forexample, consolidated UHMWPE can be soaked in 100% vitamin E or in asolution of α-Tocopherol in an alcohol, for example, ethanol orisopropanol or in an emulsion or mixture of vitamin E and water and/ordi-methyl sulfoxide (DMSO). A solution of α-Tocopherol, about 50% byweight in ethanol can be used to diffuse in to UHMWPE in contact with asupercritical fluid, such as CO₂. The balloons, for example, PeBAX®,Nylon, and PET balloons can be doped with vitamin E and irradiatedbefore, during, or after doping.

In another aspect, antioxidant doped consolidated polymeric material issubsequently annealed in a liquid or a gaseous environment and undervarious temperature and pressure conditions, for example, in boilingwater under atmospheric pressure or under pressure in order to anneal ata temperature above 100° C. and below the melting point of the polymericmaterial. In another aspect, annealing of antioxidant-doped-consolidatedpolymeric materials or antioxidant-doped-consolidated cross-linkedpolymeric materials prior to machining can be carried out at atemperature above the melting point of the polymeric material, forexample, at 150° C., 160° C., 170° C., 180° C., or higher.

The invention also relates to the following processing steps tofabricate medical devices made out of highly cross-linked polyethyleneand containing metallic pieces such as bipolar hip replacements, tibialknee inserts with reinforcing metallic and polyethylene posts,intervertebral disc systems, and for any implant that contains a surfacethat cannot be readily sterilized by a gas sterilization method.

According to one aspect of the invention, the polyethylene component ofa medical implant is in close contact with another material, such as ametallic mesh or back, a non-metallic mesh or back, a tibial tray, apatella tray, or an acetabular shell, wherein the polyethylene, such asresin powder, flakes and particles are directly compression molded tothese counter faces. For example, a polyethylene tibial insert ismanufactured by compression molding of polyethylene resin powder to atibial tray, to a metallic mesh or back or to a non-metallic mesh orback. In the latter case, the mesh is shaped to serve as a fixationinterface with the bone, through either bony in-growth or the use of anadhesive, such as polymethylmethacrylate (PMMA) bone cement. Theseshapes are of various forms including, acetabular liner, tibial tray fortotal or unicompartmental knee implants, patella tray, and glenoidcomponent, ankle, elbow or finger component. Another aspect of theinvention relates to mechanical interlocking of the molded polyethylenewith the other piece(s), for example, a metallic or a non-metallicpiece, that makes up part of the implant.

The interface geometry is crucial in that polyethylene assumes thegeometry as its consolidated shape. Polyethylene has a remarkableproperty of ‘shape memory’ due to its very high molecular weight thatresults in a high density of physical entanglements. Followingconsolidation, plastic deformation introduces a permanent shape change,which attains a preferred high entropy shape when melted. This recoveryof the original consolidated shape is due to the ‘shape memory’, whichis achieved when the polyethylene is consolidated.

The recovery of polymeric material when subjected to annealing in aneffort to quench residual free radicals is also problematic in medicaldevices that have a high degree of orientation. Balloon catheters oftencan have intended axial and radial alignment of the polymeric chains.Balloon catheters made from polyethylene benefit from the improved wearresistance generated from crosslinking when used with stents.Additionally, the use of catheters and stents coated with drugsprecludes the use of ethylene oxide sterilization in some cases; thusionizing radiation must be used, and the balloon catheter has to beprotected from the deleterious effects of free-radical inducedoxidation. Annealing of these materials close to the melt transitiontemperature would result in bulk chain motion and subsequent loss ofdimensional tolerances of the part. By diffusing 100% vitamin E or in asolution of α-Tocopherol in an alcohol, for example, ethanol orisopropanol, into the medical device, such as a balloon catheter, eitherbefore, during, or after exposure to ionizing radiation for eithercrosslinking or sterilization, the problems associated withpost-irradiation oxidation can be avoided without the need for thermaltreatment. As described herein, the balloons, for example, PeBAX®,Nylon, and PET balloons can be doped with vitamin E and irradiatedbefore, during, or after doping.

Another aspect of the invention provides that following the compressionmoldings of the polyethylene to the counterface with the mechanicalinterlock, the hybrid component is irradiated using ionizing radiationto a desired dose level, for example, about 25 kGy to about 1000 kGy,preferably between about 30 kGy and about 150 kGy, more preferablybetween about 50 kGy and about 100 kGy. Another aspect of the inventiondiscloses that the irradiation step generates residual free radicals andtherefore, a melting step is introduced thereafter to quench theresidual free radicals. Since the polyethylene is consolidated into theshape of the interface, thereby setting a ‘shape memory’ of the polymer,the polyethylene does not separate from the counterface.

In another aspect of the invention, there are provided methods ofcrosslinking polyethylene, to create a polyethylene-based medicaldevice, wherein the device is immersed in a non-oxidizing medium such asinert gas or inert fluid, wherein the medium is heated to above themelting point of the irradiated polyethylene, for example, UHMWPE (aboveabout 137° C.) to eliminate the crystalline matter and to allow therecombination/elimination of the residual free radicals. Because theshape memory of the compression molded polymer is set at themechanically interlocked interface and that memory is strengthened bythe crosslinking step, there is no significant separation at theinterface between the polyethylene and the counterface.

Another aspect of the invention provides that following the above stepsof free radical elimination, the interface between the metal and thepolymer become sterile due to the high irradiation dose level usedduring irradiation. When there is substantial oxidation on the outsidesurface of the polyethylene induced during the free radical eliminationstep or irradiation step, the device surface can be further machined toremove the oxidized surface layer. In another aspect, the inventionprovides that in the case of a post-melting machining of an implant, themelting step can be carried out in the presence of an inert gas.

Another aspect of the invention includes methods of sterilization of thefabricated device, wherein the device is further sterilized withethylene oxide, gas plasma, or the other gases, when the interface issterile but the rest of the component is not.

In another aspect, the invention discloses packaging of irradiated andantioxidant-doped medical implants or medical devices includingcompression molded implants or devices, wherein the implants or thedevices can be sterilized by ionizing radiation or gas sterilization toobtain sterile and cross-linked medical implants or medical devices.

Doping conditions: In one aspect of the invention, the vitamin E dopingstep can be carried out by soaking the UHMWPE article, implant, stockmaterial (irradiated or unirradiated) in vitamin E or a solution ofvitamin E or an emulsion of vitamin E. The vitamin E can be cycledthrough different temperatures during the doping. For example, thevitamin E can be first heated to a peak temperature, then cooled down toa valley temperature and then heated again. Peak temperature can bebetween about 50° C. and about 300° C., or between about 70° C. andabout 150° C., or about 110° C., or about 105° C., or about 100° C.Valley temperature is always lower than the peak temperature. Valleytemperature can be between about 0° C. and about 300° C., or betweenabout 20° C. and about 90° C., or about 80° C., or about 70° C., orabout 50° C., or about 25° C. The UHMWPE can be held at each peak orvalley temperatures for different time periods. Each peak temperaturecycle can be held for a time period between about 1 minute and about 30days, preferably between about 1 hour and about 3 days, more preferablybetween about 2 hours and about 24 hours, and even more preferably forabout 12 hours. Each valley temperature can be held for a time periodbetween about 1 minute and about 30 days, preferably between about 1hour and about 3 days, more preferably between 2 hours and 24 hours, andeven more preferably for about 2 hours. The cooling and heating ratesbetween cycles can be between about 1° C./min and about 100° C./min,preferably about 10° C./min. The heat-cool cycles can follow a stepfunction or a sinusoidal function or any other function. The dopingcycle can be of at least one step of heating to peak temperature, onestep of holding at peak temperature, one step of cooling to valleytemperature, or one step of holding at valley temperature.Alternatively, the number of steps can be increased to achieve a desiredlevel of vitamin E penetration into the UHMWPE. The steps can besequenced to cycle between a valley and a peak temperature. For example,soaking at 30° C. for 1 hour, heating to 105° C. or 110° C. at 10°C./min and soaking at 105° C. or 110° C. for 1 hour, cooling to 30° C.at 10° C./min, and repeating the same soak-heat-soak-cool cycle for 24times. Alternatively, the cycling can be sequenced to consecutively holdat different temperatures for different time periods. For example,soaking at 30° C. for 1 hour, heating to 90° C. at 10° C./min andsoaking at 90° C. for 1 hour, cooling to 30° C. at 10° C./min, andrepeating the same soak-heat-soak-cool cycle for 24 times but varyingthe peak temperature between 90° C. and 110° C. at every other cycle.

The above described cycling the temperature also can be used in thewater, air or other media annealing step of doped UHMWPE samples orimplants.

The above described cycling the temperature also can be used in anantioxidant/hydrophilic solvent solution or emulsion media annealingstep of doped UHMWPE samples or implants. For example, a mixture ofabout 30% vitamin E in about 70% water or about 70% di-methyl sulfoxide(DMSO) or about 70% vitamin E in about 30% water or 30% DMSO can beused. The water in the mixture also can contain NaCl.

Doping also can be completed in one step of soaking in a vitamin Esolution or a vitamin E-emulsion, for example, the soaking can becarried out at room temperature or at an elevated temperature, forexample, at about 100° C.

The vitamin E emulsion can be a mixture of vitamin E with a hydrophilicsolvent such as water and/or dimethyl sulfoxide and/or NaCl or the like.The vitamin E emulsion can have a vitamin E concentration ranging fromabout 1% to about 99%. The vitamin E emulsion also can be prepared bymixing the vitamin E in mixture of hydrophilic fluids, such as a mixtureof water and/or DMSO. The vitamin E emulsion also can be prepared byadding a solution of vitamin E into a hydrophilic fluid or a mixture ofhydrophilic fluids or a mixture of a hydrophilic fluid with NaCl.

Doping of the polymer can be carried out in a vitamin E emulsion eitherat room temperature or at a temperature between room temperature and theboiling point of the hydrophilic fluid.

The vitamin E emulsion can be salinated by adding sodium chloride (NaCl)to the hydrophilic fluid and doping can be carried out in the salinatedemulsion. Because the salination can elevate the boiling point of thehydrophilic fluid, the doping also can be carried out at a temperaturehigher than the boiling point of the non-salinated hydrophilic fluid.

The vitamin E emulsion can be doped at an elevated pressure to increasethe boiling point of the hydrophilic fluid component of the emulsion.

The vitamin E emulsion can also be mixed with sodium hydroxide (NaOH)and doping can be carried out in an alkaline emulsion. Because theaddition of NaOH can elevate the boiling point of the hydrophilic fluid,the doping also can be carried out at a temperature higher than theboiling point of the hydrophilic fluid. Since, the boiling point of ahydrophilic component of vitamin E emulsions or mixtures can beelevated, doping can be carried out at a temperature higher than theboiling point of the hydrophilic component, for example, dopingtemperature of a boiling vitamin E-water emulsion can be higher than100° C., for example, about 105° C. or about 110° C.

Doping also can be carried out at an elevated pressure by soaking thepolymer in vitamin E, vitamin E solution, or vitamin E emulsion, or amixture thereof.

Doping and post-doping annealing: Referring to FIGS. 6A and 6B, thepenetration depth of vitamin E into UHMWPE increased with increasingtemperature of doping. Annealing in boiling water subsequent to dopingincreased the penetration depth of the vitamin E into UHMWPE. It alsoreduced the surface concentration of vitamin E. This method of annealingin boiling water can be used to increase the uniformity of the vitamin Edistribution in UHMWPE. If desired, the decrease in the near surfaceconcentration of vitamin E can be increased with subsequent additionaldoping cycles of vitamin E. If desired, the additional doping cyclesalso can be followed by annealing cycles, for example, in boiling water.

The annealing of antioxidant-doped UHMWPE also can be carried out inwater at other temperatures, such as between room temperature andboiling point of water. Alternatively, the water also can be at a highertemperature, either in the form of steam or liquid. The liquid form ofwater at temperatures above the normal boiling point can be achieved byincreasing the pressure. Irradiated and antioxidant-doped UHMWPE can beannealed in a pressure chamber in water at elevated temperatures andpressures to maintain the liquid or steam/gaseous state of water.

Referring to FIGS. 7A and 7B, the depth-profiles of sensitive vitamin Eindex (sensVitE) indicate doping at 100° C. in vitamin E emulsionresulted in a higher vitamin E surface concentration and a deepervitamin E penetration than the UHMWPE cubes that were doped in vitamin Ealone. Doping for 24 hours at 100° C. in the vitamin E emulsion resultedin a diffusion profile equivalent to a 72 hours of doping in vitamin Ealone (see FIG. 7B).

Annealing of vitamin E emulsion-doped UHMWPE in boiling water subsequentto doping can increase the penetration depth of the vitamin E intoUHMWPE. It also can reduce the surface concentration of vitamin E. Thismethod of annealing vitamin E emulsion-doped UHMWPE in boiling water canbe used to increase the uniformity of the vitamin E distribution inUHMWPE. If desired, the decrease in the near surface concentration ofvitamin E can be increased with subsequent additional doping cycles ofvitamin E or vitamin E emulsion. If desired, the additional dopingcycles also can be followed by annealing cycles, for example, in boilingwater or in boiling vitamin E emulsion.

The annealing of antioxidant-emulsion-doped UHMWPE also can be carriedout in antioxidant-emulsion at other temperatures, such as between roomtemperature and boiling point of the hydrophilic component of theemulsion. Alternatively, the antioxidant-emulsion also can be at ahigher temperature, either in the form of steam or liquid. For example,the liquid form of the hydrophilic component of the emulsion can be at atemperature above its normal boiling point, which can be achieved byincreasing the pressure. Irradiated and antioxidant-emulsion-dopedUHMWPE can be annealed in a pressure chamber containing the emulsion atelevated temperatures and pressures.

The above annealing methods also can be applied to a finished article,such as a medical implant. The implant can be machined from anirradiated UHMWPE. Alternatively, the implant can be direct compressionmolded from UHMWPE powder and subsequently irradiated. The implant canbe doped with vitamin E or vitamin E emulsion and subsequently annealed.In another aspect, the doping can be carried out by soaking the implantin vitamin E, vitamin E emulsion, or vitamin E solution, heated to atemperature between room temperature and about 145° C., preferablybetween about 50° C. and about 140° C., more preferably between about90° C. and about 120° C., and even more preferably at about 105° C. orabout 110° C. The doping can be carried out for a time period betweenabout 1 minute and about 30 days, preferably between about 1 hour andabout 3 days, more preferably between about 10 hours and about 3 days,and even more preferably for about 24 hours. Subsequent to doping, theannealing can be carried out in a liquid medium, such as water, mineraloil, vitamin E emulsion, vitamin E solution, etc. The annealing can becarried out by soaking the implant in the liquid medium, for example, inwater or in vitamin E emulsion, or in vitamin E solution, at an elevatedtemperature of between about room temperature and about 100° C., morepreferably between about 50° C. and about 100° C., and even morepreferably at about 100° C. The annealing in the liquid medium, forexample, in water or in vitamin E emulsion, also can be carried out insteam at different temperatures. The annealing can be carried out for atime period between about 1 minute and about 30 days, preferably betweenabout 1 hour and about 3 days, more preferably between about 10 hoursand about 3 days, and even more preferably for about 24 hours.

The post-doping annealing, for example, in boiling water, results indeeper antioxidant (for example, α-tocopherol, such as vitamin E)penetration into the irradiated UHMWPE. The deeper penetration ofantioxidant is advantageous in many ways. Deeper penetration of theantioxidant protects a thicker surface layer of the polyethylene againstoxidation. In some cases, if the penetration is deep enough, a minimumconcentration of antioxidant is achieved throughout the irradiatedUHMWPE and also provide oxidation resistance throughout the irradiatedUHMWPE.

Following annealing, the implant can be further doped with vitamin E orvitamin E emulsion to increase the surface concentration of vitamin Ethat may have decreased during the annealing cycle.

The annealing cycle can be followed by an industrial washing cycle, forexample, a dishwasher cycle. The washing cycle also can be considered asthe annealing cycle.

The annealing of doped polymeric material can be conducted under anysuitable liquid or gaseous environment, under various temperature andpressure conditions, for example, in boiling water under atmosphericpressure or under pressure in order to anneal at a temperature above100° C. and below the melting point of UHMWPE. In another aspect,annealing of antioxidant-doped-polymeric materials orantioxidant-doped-cross-linked polymeric materials prior to machiningcan be carried out at a temperature above the melting point of thepolymeric material, for example, at 150° C., 160° C., 170° C., 180° C.,or higher.

The annealing of doped polymeric material also can be carried out in afluid, for example, water, vitamin E emulsion, vitamin E solution, ormineral oil, under pressure at a temperature above 100° C. and below themelting point of the polymeric material or above the melting point ofthe polymeric materials prior to machining, for example, at 150° C.,160° C., 170° C., 180° C., or higher.

The above doping and post-doping annealing steps can also be used withan annealing step, as described above, before prior to doping; forexample, the polymeric material or the medical implant can be boiled inwater and then doped, or boiled in water and then doped, and annealed.

The above doping and post-doping annealing techniques also can be usedwith any anti-oxidant or any other additive.

Methods of doping, post-doping annealing, and making oxidation resistantpolymeric material are also disclosed in U.S. application Ser. No.10/757,551, filed Jan. 15, 2004, the entirety of which is incorporatedherewith by reference.

Definitions: Definitions of various terms used in this application areprovided herewith in order to illustrate certain aspects of theinvention.

“Antioxidant” refers to what is known in the art as (see, for example,WO 01/80778, U.S. Pat. No. 6,448,315). Alpha- and delta-tocopherol;propyl, octyl, or dedocyl gallates; lactic, citric, and tartaric acidsand their salts; orthophosphates, tocopherol acetate. Preferably vitaminE.

The term “antioxidant-emulsion” or “antioxidant-solution” for example,“vitamin E emulsion” or “vitamin E solution” refers to a mixture orsolution of vitamin E (α-Tocopherol) and water, mineral oil, or anyother hydrophilic fluid and/or di-methyl sulfoxide (DMSO) and/or NaCland/or NaOH or a mixture thereof. The mixture can be a mixture of theantioxidant, for example, vitamin E, in an alcohol, for example, ethanolor isopropanol in a hydrophilic fluid or a mixture of the hydrophilicfluids. The concentration of an antioxidant, for example, vitamin E, inan emulsion can vary between about 1% (by volume) and 99% (by volume).

“Supercritical fluid” refers to what is known in the art, for example,supercritical propane, acetylene, carbon dioxide (CO₂). In thisconnection the critical temperature is that temperature above which agas cannot be liquefied by pressure alone. The pressure under which asubstance may exist as a gas in equilibrium with the liquid at thecritical temperature is the critical pressure. Supercritical fluidcondition generally means that the fluid is subjected to such atemperature and such a pressure that a supercritical fluid and thereby asupercritical fluid mixture is obtained, the temperature being above thesupercritical temperature, which for CO₂ is 31.3° C., and the pressurebeing above the supercritical pressure, which for CO₂ is 73.8 bar. Morespecifically, supercritical condition refers to a condition of amixture, for example, UHMWPE with an antioxidant, at an elevatedtemperature and pressure, when a supercritical fluid mixture is formedand then evaporate CO₂ from the mixture, UHMWPE doped with anantioxidant is obtained (see, for example, U.S. Pat. No. 6,448,315 andWO 02/26464)

The term “compression molding” as referred herein related generally towhat is known in the art and specifically relates to high temperaturemolding polymeric material wherein polymeric material is in any physicalstate, including powder form, is compressed into a slab form or mold ofa medical implant, for example, a tibial insert, an acetabular liner, aglenoid liner, a patella, or an unicompartmental insert, can bemachined.

The term “direct compression molding” as referred herein relatedgenerally to what is known in the art and specifically relates tomolding applicable in polyethylene-based devices, for example, medicalimplants wherein polyethylene in any physical state, including powderform, is compressed to solid support, for example, a metallic back,metallic mesh, or metal surface containing grooves, undercuts, orcutouts. The compression molding also includes high temperaturecompression molding of polyethylene at various states, including resinpowder, flakes and particles, to make a component of a medical implant,for example, a tibial insert, an acetabular liner, a glenoid liner, apatella, or an unicompartmental insert.

The term “mechanically interlocked” refers generally to interlocking ofpolyethylene and the counterface, that are produced by various methods,including compression molding, heat and irradiation, thereby forming aninterlocking interface, resulting into a ‘shape memory’ of theinterlocked polyethylene. Components of a device having such aninterlocking interface can be referred to as a “hybrid material”.Medical implants having such a hybrid material, contain a substantiallysterile interface.

The term “substantially sterile” refers to a condition of an object, forexample, an interface or a hybrid material or a medical implantcontaining interface(s), wherein the interface is sufficiently sterileto be medically acceptable, i.e., will not cause an infection or requirerevision surgery.

“Metallic mesh” refers to a porous metallic surface of various poresizes, for example, 0.1-3 mm. The porous surface can be obtained throughseveral different methods, for example, sintering of metallic powderwith a binder that is subsequently removed to leave behind a poroussurface; sintering of short metallic fibers of diameter 0.1-3 mm; orsintering of different size metallic meshes on top of each other toprovide an open continuous pore structure.

“Bone cement” refers to what is known in the art as an adhesive used inbonding medical devices to bone. Typically, bone cement is made out ofpolymethylmethacrylate (PMMA).

“High temperature compression molding” refers to the compression moldingof polyethylene in any form, for example, resin powder, flakes orparticles, to impart new geometry under pressure and temperature. Duringthe high temperature (above the melting point of polyethylene)compression molding, polyethylene is heated to above its melting point,pressurized into a mold of desired shape and allowed to cool down underpressure to maintain a desired shape.

“Shape memory” refers to what is known in the art as the property ofpolyethylene, for example, an UHMWPE, that attains a preferred highentropy shape when melted. The preferred high entropy shape is achievedwhen the resin powder is consolidated through compression molding.

The phrase “substantially no detectable residual free radicals” refersto a state of a polyethylene component, wherein enough free radicals areeliminated to avoid oxidative degradation, which can be evaluated byelectron spin resonance (ESR). The phrase “detectable residual freeradicals” refers to the lowest level of free radicals detectable by ESRor more. The lowest level of free radicals detectable withstate-of-the-art instruments is about 10¹⁴ spins/gram and thus the term“detectable” refers to a detection limit of 10¹⁴ spins/gram by ESR.

The terms “about” or “approximately” in the context of numerical valuesand ranges refers to values or ranges that approximate or are close tothe recited values or ranges such that the invention can perform asintended, such as having a desired degree of crosslinking and/or adesired lack of free radicals, as is apparent to the skilled person fromthe teachings contained herein. This is due, at least in part, to thevarying properties of polymer compositions. Thus these terms encompassvalues beyond those resulting from systematic error.

Polymeric Material: Ultra-high molecular weight polyethylene (UHMWPE)refers to linear non-branched chains of ethylene having molecularweights in excess of about 500,000, preferably above about 1,000,000,and more preferably above about 2,000,000. Often the molecular weightscan reach about 8,000,000 or more. By initial average molecular weightis meant the average molecular weight of the UHMWPE starting material,prior to any irradiation. See U.S. Pat. No. 5,879,400, PCT/US99/16070,filed on Jul. 16, 1999, and PCT/US97/02220, filed Feb. 11, 1997.

The products and processes of this invention also apply to various typesof polymeric materials, for example, any polyolefin, includinghigh-density-polyethylene, low-density-polyethylene,linear-low-density-polyethylene, ultra-high molecular weightpolyethylene (UHMWPE), or mixtures thereof. Polymeric materials, as usedherein, also applies to polyethylene of various forms, for example,resin powder, flakes, particles, powder, or a mixture thereof, or aconsolidated form derived from any of the above.

Crosslinking Polymeric Material: Polymeric Materials, for example,UHMWPE can be cross-linked by a variety of approaches, including thoseemploying cross-linking chemicals (such as peroxides and/or silane)and/or irradiation. Preferred approaches for cross-linking employirradiation. Cross-linked UHMWPE also can be obtained according to theteachings of U.S. Pat. No. 5,879,400, U.S. Pat. No. 6,641,617, andPCT/US97/02220.

Consolidated Polymeric Material: “Consolidated polymeric materialrefers” to a solid, consolidated bar stock, solid material machined fromstock, or semi-solid form of polymeric material derived from any formsas described herein, for example, resin powder, flakes, particles, or amixture thereof, that can be consolidated. The consolidated polymericmaterial also can be in the form of a slab, block, solid bar stock,machined component, film, tube, balloon, pre-form, implant, or finishedmedical device.

The term “non-permanent device” refers to what is known in the art as adevice that is intended for implantation in the body for a period oftime shorter than several months. Some non-permanent devices could be inthe body for a few seconds to several minutes, while other may beimplanted for days, weeks, or up to several months. Non-permanentdevices include catheters, tubing, intravenous tubing, and sutures, forexample.

“Pharmaceutical compound”, as described herein, refers to a drug in theform of a powder, suspension, emulsion, particle, film, cake, or moldedform. The drug can be free-standing or incorporated as a component of amedical device.

The term “pressure chamber” refers to a vessel or a chamber in which theinterior pressure can be raised to levels above atmospheric pressure.

The term “packaging” refers to the container or containers in which amedical device is packaged and/or shipped. Packaging can include severallevels of materials, including bags, blister packs, heat-shrinkpackaging, boxes, ampoules, bottles, tubes, trays, or the like or acombination thereof. A single component may be shipped in severalindividual types of package, for example, the component can be placed ina bag, which in turn is placed in a tray, which in turn is placed in abox. The whole assembly can be sterilized and shipped. The packagingmaterials include, but not limited to, vegetable parchments, multi-layerpolyethylene, Nylon 6, polyethylene terephthalate (PET), and polyvinylchloride-vinyl acetate copolymer films, polypropylene, polystyrene, andethylene-vinyl acetate (EVA) copolymers.

The term “sealing” refers to the process of isolating a chamber or apackage from the outside atmosphere by closing an opening in the chamberor the package. Sealing can be accomplished by a variety of means,including application of heat (for example, thermally-sealing), use ofadhesive, crimping, cold-molding, stapling, or application of pressure.

The term “blister packs” refers to a packaging comprised of a rigidplastic bowl with a lid or the like that is either peeled or puncturedto remove the packaged contents. The lid is often made of aluminum, or agas-permeable membrane such as a Tyvek. The blister packs are oftenblow-molded, a process where the plastic is heated above its deformationtemperature, at which point pressurized gas forces the plastic into therequired shape.

The term “heat-shrinkable packaging” refers to plastic films, bags, ortubes that have a high degree of orientation in them. Upon applicationof heat, the packaging shrinks down as the oriented chains retract,often wrapping tightly around the medical device.

The term “intervertebral disc system” refers to an artificial disc thatseparates the vertebrae in the spine. This system can either be composedof one type of material, or can be a composite structure, for example,cross-linked UHMWPE with metal edges.

The term “balloon catheters” refers to what is known in the art as adevice used to expand the space inside blood vessels or similar. Ballooncatheters are usually thin wall polymeric devices with an inflatabletip, and can expand blocked arteries, stents, or can be used to measureblood pressure. Commonly used polymeric balloons include, for example,polyether-block co-polyamide polymer (PeBAX®), Nylon, and polyethyleneterephthalate (PET) balloons. Commonly used polymeric material used inthe balloons and catheters include, for example, co-polymers ofpolyether and polyamide (for example, PeBAX®), Polyamides, Polyesters(for example, PET), and ethylene vinyl alcohol (EVA) used in catheterfabrication.

Medical device tubing: Materials used in medical device tubing,including an intravenous tubing include, polyvinyl chloride (PVC),polyurethane, polyolefins, and blends or alloys such as thermoplasticelastomers, polyamide/imide, polyester, polycarbonate, or variousfluoropolymers.

The term “stent” refers to what is known in the art as a metallic orpolymeric cage-like device that is used to hold bodily vessels, such asblood vessels, open. Stents are usually introduced into the body in acollapsed state, and are inflated at the desired location in the bodywith a balloon catheter, where they remain.

“Melt transition temperature” refers to the lowest temperature at whichall the crystalline domains in a material disappear.

The term “interface” in this invention is defined as the niche inmedical devices formed when an implant is in a configuration where acomponent is in contact with another piece (such as a metallic or anon-metallic component), which forms an interface between the polymerand the metal or another polymeric material. For example, interfaces ofpolymer-polymer or polymer-metal are in medical prosthesis, such asorthopedic joints and bone replacement parts, for example, hip, knee,elbow or ankle replacements.

Medical implants containing factory-assembled pieces that are in closecontact with the polyethylene form interfaces. In most cases, theinterfaces are not readily accessible to ethylene oxide gas or the gasplasma during a gas sterilization process.

Irradiation: In one aspect of the invention, the type of radiation,preferably ionizing, is used. According to another aspect of theinvention, a dose of ionizing radiation ranging from about 25 kGy toabout 1000 kGy is used. The radiation dose can be about 25 kGy, about 50kGy, about 65 kGy, about 75 kGy, about 85 kGy, about 100 kGy, about 150kGy, about 200 kGy, about 300 kGy, about 400 kGy, about 500 kGy, about600 kGy, about 700 kGy, about 800 kGy, about 900 kGy, or about 1000 kGy,or above 1000 kGy, or any integer thereabout or therebetween.Preferably, the radiation dose can be between about 25 kGy and about 150kGy or between about 50 kGy and about 100 kGy. These types of radiation,including gamma and/or electron beam, kills or inactivates bacteria,viruses, or other microbial agents potentially contaminating medicalimplants, including the interfaces, thereby achieving product sterility.The irradiation, which may be electron or gamma irradiation, inaccordance with the present invention can be carried out in airatmosphere containing oxygen, wherein the oxygen concentration in theatmosphere is at least 1%, 2%, 4%, or up to about 22%, or any integerthereabout or therebetween. In another aspect, the irradiation can becarried out in an inert atmosphere, wherein the atmosphere contains gasselected from the group consisting of nitrogen, argon, helium, neon, orthe like, or a combination thereof. The irradiation also can be carriedout in a vacuum.

In accordance with a preferred feature of this invention, theirradiation may be carried out in a sensitizing atmosphere. This maycomprise a gaseous substance which is of sufficiently small molecularsize to diffuse into the polymer and which, on irradiation, acts as apolyfunctional grafting moiety. Examples include substituted orunsubstituted polyunsaturated hydrocarbons; for example, acetylenichydrocarbons such as acetylene; conjugated or unconjugated olefinichydrocarbons such as butadiene and (meth)acrylate monomers; sulfurmonochloride, with chloro-tri-fluoroethylene (CTFE) or acetylene beingparticularly preferred. By “gaseous” is meant herein that thesensitizing atmosphere is in the gas phase, either above or below itscritical temperature, at the irradiation temperature.

Metal Piece: In accordance with the invention, the piece forming aninterface with polymeric material is, for example, a metal. The metalpiece in functional relation with polyethylene, according to the presentinvention, can be made of a cobalt chrome alloy, stainless steel,titanium, titanium alloy or nickel cobalt alloy, for example.

Non-metallic Piece: In accordance with the invention, the piece formingan interface with polymeric material is, for example, a non-metal. Thenon-metal piece in functional relation with polyethylene, according tothe present invention, can be made of ceramic material, for example.

The term “inert atmosphere” refers to an environment having no more than1% oxygen and more preferably, an oxidant-free condition that allowsfree radicals in polymeric materials to form cross links withoutoxidation during a process of sterilization. An inert atmosphere is usedto avoid O₂, which would otherwise oxidize the medical device comprisinga polymeric material, such as UHMWPE. Inert atmospheric conditions suchas nitrogen, argon, helium, or neon are used for sterilizing polymericmedical implants by ionizing radiation.

Inert atmospheric conditions such as nitrogen, argon, helium, neon, orvacuum are also used for sterilizing interfaces of polymeric-metallicand/or polymeric-polymeric in medical implants by ionizing radiation.

Inert atmospheric conditions also refers to an inert gas, inert fluid,or inert liquid medium, such as nitrogen gas or silicon oil.

Anoxic environment: “Anoxic environment” refers to an environmentcontaining gas, such as nitrogen, with less than 21%-22% oxygen,preferably with less than 2% oxygen. The oxygen concentration in ananoxic environment also can be at least 1%, 2%, 4%, 6%, 8%, 10%, 12%14%, 16%, 18%, 20%, or up to about 22%, or any integer thereabout ortherebetween.

The term “vacuum” refers to an environment having no appreciable amountof gas, which otherwise would allow free radicals in polymeric materialsto form cross links without oxidation during a process of sterilization.A vacuum is used to avoid O₂, which would otherwise oxidize the medicaldevice comprising a polymeric material, such as UHMWPE. A vacuumcondition can be used for sterilizing polymeric medical implants byionizing radiation.

A vacuum condition can be created using a commercially available vacuumpump. A vacuum condition also can be used when sterilizing interfaces ofpolymeric-metallic and/or polymeric-polymeric in medical implants byionizing radiation.

Residual Free Radicals: “Residual free radicals” refers to free radicalsthat are generated when a polymer is exposed to ionizing radiation suchas gamma or e-beam irradiation. While some of the free radicalsrecombine with each other to from crosslinks, some become trapped incrystalline domains. The trapped free radicals are also known asresidual free radicals.

According to one aspect of the invention, the levels of residual freeradicals in the polymer generated during an ionizing radiation (such asgamma or electron beam) is preferably determined using electron spinresonance and treated appropriately to reduce the free radicals.

Sterilization: One aspect of the present invention discloses a processof sterilization of medical implants containing polymeric material, suchas cross-linked UHMWPE. The process comprises sterilizing the medicalimplants by ionizing sterilization with gamma or electron beamradiation, for example, at a dose level ranging from 25-70 kGy, or bygas sterilization with ethylene oxide or gas plasma.

Another aspect of the present invention discloses a process ofsterilization of medical implants containing polymeric material, such ascross-linked UHMWPE. The process comprises sterilizing the medicalimplants by ionizing sterilization with gamma or electron beamradiation, for example, at a dose level ranging from 25-200 kGy. Thedose level of sterilization is higher than standard levels used inirradiation. This is to allow crosslinking or further crosslinking ofthe medical implants during sterilization.

In another aspect, the invention discloses a process of sterilizingmedical implants containing polymeric material, such as cross-linkedUHMWPE, that is in contact with another piece, including polymericmaterial consolidated by compression molding to another piece, therebyforming an interface and an interlocked hybrid material, comprisingsterilizing an interface by ionizing radiation; heating the medium toabove the melting point of the irradiated UHMWPE (above about 137° C.)to eliminate the crystalline matter and allow for therecombination/elimination of the residual free radicals; and sterilizingthe medical implant with a gas, for example, ethylene oxide or gasplasma.

Heating: One aspect of the present invention discloses a process ofincreasing the uniformity of the antioxidant following doping inpolymeric component of a medical implant during the manufacturingprocess by heating for a time period depending on the meltingtemperature of the polymeric material. For example, the preferredtemperature is about 137° C. or less. Another aspect of the inventiondiscloses a heating step that can be carried in the air, in anatmosphere, containing oxygen, wherein the oxygen concentration is atleast 1%, 2%, 4%, or up to about 22%, or any integer thereabout ortherebetween. In another aspect, the invention discloses a heating stepthat can be carried while the implant is in contact with an inertatmosphere, wherein the inert atmosphere contains gas selected from thegroup consisting of nitrogen, argon, helium, neon, or the like, or acombination thereof. In another aspect, the invention discloses aheating step that can be carried while the implant is in contact with anon-oxidizing medium, such as an inert fluid medium, wherein the mediumcontains no more than about 1% oxygen. In another aspect, the inventiondiscloses a heating step that can be carried while the implant is in avacuum.

In another aspect of this invention, there is described the heatingmethod of implants to reduce increase the uniformity of the antioxidant.The medical device comprising a polymeric raw material, such as UHMWPE,is generally heated to a temperature of about 137° C. or less followingthe step of doping with the antioxidant. The medical device is keptheated in the inert medium until the desired uniformity of theantioxidant is reached.

The term “below the melting point” or “below the melt” refers to atemperature below the melting point of a polyethylene, for example,UHMWPE. The term “below the melting point” or “below the melt” refers toa temperature less than 145° C., which may vary depending on the meltingtemperature of the polyethylene, for example, 145° C., 140° C. or 135°C., which again depends on the properties of the polyethylene beingtreated, for example, molecular weight averages and ranges, batchvariations, etc. The melting temperature is typically measured using adifferential scanning calorimeter (DSC) at a heating rate of 10° C. perminute. The peak melting temperature thus measured is referred to asmelting point and occurs, for example, at approximately 137° C. for somegrades of UHMWPE. It may be desirable to conduct a melting study on thestarting polyethylene material in order to determine the meltingtemperature and to decide upon an irradiation and annealing temperature.

The term “annealing” refers to heating the polymer below its peakmelting point. Annealing time can be at least 1 minute to several weekslong. In one aspect the annealing time is about 4 hours to about 48hours, preferably 24 to 48 hours and more preferably about 24 hours.“Annealing temperature” refers to the thermal condition for annealing inaccordance with the invention.

The term “annealing” also refers to heating antioxidant-doped orantioxidant-emulsion-doped polymeric material or UHMEPE-based materialunder a liquid or gaseous environment under various temperature andpressure conditions. For example, annealing can be carried out in wateror antioxidant-emulsion or antioxidant-solution at temperature betweenroom temperature boiling point of water or the hydrophilic component ofthe emulsion under atmospheric pressure, or under pressure at atemperature above 100° C. and below the melting point of the polymericmaterial. Annealing of antioxidant-doped-polymeric materials orantioxidant-doped-cross-linked polymeric materials prior to machiningalso can be carried out at a temperature above the melting point of thepolymeric material, for example, at 150° C., 160° C., 170° C., 180° C.,190° C., 200° C., or higher.

Annealing time in liquid or gaseous environment can be carried out for atime period between about 1 minute and about 30 days, preferably betweenabout 1 hour and about 3 days, more preferably between about 10 hoursand about 3 days, and even more preferably for about 24 hours.

Annealing of polymeric material or UHMWPE-based material also can bedone in a fluid under pressure at a temperature above 100° C. and belowthe melting point of the polymeric material. Annealing of polymericmaterial or UHMWPE-based material prior to machining also can be carriedout at a temperature above the melting point of the material, forexample, at 150° C., 160° C., 170° C., 180° C., 190° C., 200° C., orhigher.

The term “fluid” refers to liquids and gases, including mineral oil,water, alcohols, and dimethyl sulfoxide, steam, vapor, aerosols,emulsions, solutions, mixtures, and the like.

The term “contacted” includes physical proximity with or touching suchthat the sensitizing agent can perform its intended function.Preferably, a polyethylene composition or pre-form is sufficientlycontacted such that it is soaked in the sensitizing agent, which ensuresthat the contact is sufficient. Soaking is defined as placing the samplein a specific environment for a sufficient period of time at anappropriate temperature, for example, soaking the sample in a solutionof an antioxidant. The environment is heated to a temperature rangingfrom room temperature to a temperature below or above the melting pointof the material. The contact period ranges from at least about 1 minuteto several weeks and the duration depending on the temperature of theenvironment.

The term “non-oxidizing” refers to a state of polymeric material havingan oxidation index (A.U.) of less than about 0.5 following agingpolymeric materials for 5 weeks in air at 80° C. oven. Thus, anon-oxidizing cross-linked polymeric material generally shows anoxidation index (A.U.) of less than about 0.5 after the aging period.

The term “doping” refers to a process well known in the art (see, forexample, U.S. Pat. Nos. 6,448,315 and 5,827,904) and as described above.In this connection, doping generally refers to contacting a polymericmaterial or a medical implant containing polymeric material with anantioxidant under certain conditions, as set forth herein, for example,doping UHMWPE with an antioxidant under supercritical conditions.

More specifically, consolidated polymeric material can be doped with anantioxidant by soaking the material in a solution of the antioxidant.This allows the antioxidant to diffuse into the polymer. For instance,the material can be soaked in 100% antioxidant. The material also can besoaked in an antioxidant solution where a carrier solvent can be used todilute the antioxidant concentration. To increase the depth of diffusionof the antioxidant, the material can be doped for longer durations, athigher temperatures, at higher pressures, and/or in presence of asupercritical fluid.

The doping process can involve soaking of a polymeric material, medicalimplant or device with an antioxidant, such as vitamin E, for about anhour up to several days, preferably for at least about one hour to 24hours, more preferably for at least one hour to 16 hours. Theantioxidant can be heated to room temperature or up to about 160° C. andthe doping can be carried out at room temperature or up to about 160° C.Preferably, the antioxidant can be heated to 105° C. or 110° C. and thedoping is carried out at 105° C. or 110° C.

The doping step can be followed by a heating step in air or in anoxicenvironment to improve the uniformity of the antioxidant within thepolymeric material, medical implant or device. The heating may becarried out above or below or at the peak melting point. For example,doping of polymeric materials prior to machining can be carried out at atemperature above the melting point of the polymeric material, forexample, at 150° C., 160° C., 170° C., 180° C., 190° C., 200° C., orhigher.

In another aspect of the invention the medical device is cleaned beforepackaging and sterilization.

The invention is further described by the following examples, which donot limit the invention in any manner.

EXAMPLES

Vitamin E: Vitamin E (Acros™ 99% D-α-Tocopherol, Fisher Brand), was usedin the experiments described herein, unless otherwise specified. Thevitamin E used is very light yellow in color and is a viscous fluid atroom temperature. Its melting point is 2-3° C.

Example 1 Consolidation of UHMWPE Resin Mixed with Vitamin E

Vitamin E was dissolved in ethanol to create a solution with 10% (w/v)vitamin E concentration. The vitamin E-ethanol solution was thendry-blended with GUR 1050 ultra-high molecular weight polyethylene(UHMWPE) resin. Two batches were prepared: one with vitamin Econcentration of 0.1% (w/v) and the other with 0.3% (w/v). The vitamin Econcentrations were measured after evaporation of ethanol. Both batcheswere than consolidated on a Carver laboratory bench pressed at atemperature of 230° C. in air. The consolidated blocks were discolored.The 0.1% (w/v) solution appeared dark yellow and the 0.3% (w/v) solutionhad a brown color. The discoloration was uniform throughout theconsolidated UHMWPE blocks.

The discoloration was thought to be the result of the degradation ofvitamin E when heated in presence of oxygen.

Example 2 Discoloration of Vitamin E when Exposed to Heat in Air or inVacuum

An experiment was carried out to determine if the vitamin Ediscoloration is due to exposure to air at elevated temperatures and ifthe discoloration could be avoided by heating vitamin E under vacuum.

One drop of vitamin E solution, as described herein, was placed on alaboratory glass slide. The glass slide was then heated in an airconvection oven to 180° C. for 1 hour in air. The vitamin E changed itscolor to a dark brown. The discoloration was most probably due to thedegradation of the vitamin E.

One drop of vitamin E was placed on a laboratory glass slide. The glassslide was then heated in a vacuum oven to 180° C. for 1 hour undervacuum. In contrast to heating in air, vitamin E showed no discerniblecolor change following heating in vacuum. Therefore, in the absence ofair or oxygen, heat treatment of vitamin E results in no discernablecolor change.

Example 3 Consolidation of UHMWPE/Vitamin E in Anoxic Environment

Vitamin E is dissolved in ethanol to create a solution. GUR1050polyethylene resin is degassed either in vacuum or is kept in an anoxicenvironment to substantially remove the dissolved oxygen. The vitaminE-ethanol solution is then dry-blended with GUR1050 polyethylene resin.Two batches are prepared, one with degassed GUR1050 and the other withthe as-received GUR1050 polyethylene resin. The dry-blended mixtures arethen separately consolidated on a Carver laboratory bench press.Consolidation can be carried out in an anoxic environment to minimizethe discoloration of the consolidated stock.

Example 4 Pin-On-Disk (POD) Wear Test of Pins Treated with 0.1% and 0.3%Vitamin E

An experiment was carried out to determine the effects of vitamin E oncrosslinking efficiency of UHMWPE. Vitamin E (α-tocopherol) was mixedwith GUR1050 UHMWPE powder, in two concentrations, for example, 0.1% and0.3% weight/volume, and consolidated. The consolidation of UHMWPE intoblocks was achieved by compression molding. One additional consolidationwas carried out without vitamin E additive, to use as a control. Thethree consolidated blocks were machined into halves and one half of eachwas packaged in vacuum and irradiated to 100 kGy with gamma radiation(Steris, Northborough, Mass.).

Cylindrical pins, 9 mm in diameter and 13 mm in length, were cut out ofthe irradiated blocks. The pins were first subjected to acceleratedaging at 80° C. for 5 weeks in air and subsequently tested on abi-directional pin-on-disk (POD). The POD test was run for a total of 2million cycles with gravimetric assessment of wear at every 0.5 millioncycles. The test was run at a frequency of 2 Hz with bovine serum, as alubricant.

The typical wear rate of UHMWPE with no radiation history and no vitaminE is around 8.0 milligram per million cycles. The wear rates for the 100kGy irradiated vitamin E added pins were 2.10±0.17 and 5.01±0.76milligram per million cycles for the 0.1% and 0.3% vitamin Econcentrations, respectively. The reduction in wear resistance is lesswith higher vitamin E content.

By increasing vitamin E content, the radiation induced long-termoxidative instability of polyethylene can be decreased. In other words,improved resistance to post-irradiation oxidation of UHMWPE can beachieved by blending with vitamin E. However, the crosslink density ofUHMWPE, achieved by a high irradiation dose, decreases with increasingconcentration of vitamin E content in the mixture.

Example 5 Diffusion of Vitamin E into Consolidated Polyethylene

A drop of vitamin E was placed on a machined surface of consolidatedGUR1050 UHMWPE in air. In six hours, the vitamin E drop was no longervisible on that machined surface, indicating that it had diffused intothe polyethylene.

Example 6 Diffusion of Vitamin E into Irradiated Polyethylene

Compression molded GUR1050 UHMWPE (Perplas, Lanchashire, UK) wasirradiated using gamma radiation at a dose level of 100 kGy. Cylindricalpins (n=10) of 9 mm diameter and 13 mm height were machined from theirradiated stock. One of the basal surfaces of five of the pins (n=5)were wetted with vitamin E. The other five pins served as controlsamples. The two groups of pins were left in air at room temperature for16 hours. They were then placed in a convection oven at 80° C. in airfor accelerated aging.

The aged pins were removed from the oven after five weeks to determinethe extent of oxidation. The pins were first cut in half along the axisof the cylinder. One of the cut surfaces was then microtomed (150-200micrometer) and a BioRad UMA 500 infra-red microscope was used tocollect infra-red spectrum as a function of distance away from the edgecorresponding to one of the basal surfaces of the cylinder. In the caseof the vitamin E treated pins, the oxidation level was quantified fromthe basal surface that was wetted with vitamin E.

Oxidation index was calculated by normalizing the area under thecarbonyl vibration (1740 cm⁻¹) to that under the methylene vibration at1370 cm⁻¹, after subtracting the corresponding baselines.

The oxidation levels were substantially reduced by the application ofvitamin E onto the surface of irradiated polyethylene. Therefore, thismethod can be used to improve the long-term oxidative stability ofirradiated polyethylene, for example, in medical devices containingpolymeric material.

Example 7 Diffusion of Vitamin E into Polyethylene Followed byIrradiation

Compression molded GUR1050 UHMWPE (Perplas, Lanchashire, UK) wasmachined into cubes (n=4) of 19 mm a side. The surfaces of two cubeswere wetted with vitamin E and left at room temperature for 16 hours.Two other cubes were left without addition of vitamin E. One cube ofeach group with and without vitamin E were packaged in an anoxicenvironment (for example, about 2% oxygen) and the remaining five cubesof each group were packaged in air. The cubes were irradiated usinggamma radiation at a dose level of 100 kGy in their respectivepackaging.

The irradiated cubes were removed from the packages and placed in anoven at 80° C. in the air for accelerated aging.

The aged cubes were removed from the oven after five weeks to determinethe extent of oxidation. The cubes were first cut into halves. One ofthe cut surfaces was then microtomed (150-200 micrometer) and a BioRadUMA 500 infra-red microscope was used to collect infra-red spectrum as afunction of distance away from one of the edges.

Oxidation index was calculated by normalizing the area under thecarbonyl vibration (1740 cm⁻¹) to that under the methylene vibration at1370 cm⁻¹, after subtracting the corresponding baselines.

The oxidation levels were substantially reduced by the application ofvitamin E onto the surface of polyethylene prior to irradiation in airor anoxic environment. Therefore, this method can be used to improve thelong-term oxidative stability of polyethylene that may subsequently beirradiated to sterilization and/or crosslinking polymeric material, forexample, medical devices containing polymeric material.

Example 8 Fabrication of a Highly Cross-Linked Medical Device

A tibial knee insert is machined from compression molded GUR1050 UHMWPE.The insert is then soaked in 100% vitamin E or a solution of vitamin E.The diffusion of vitamin E into the insert may be accelerated byincreasing temperature and/or pressure, which can be carried out eitherin air or inert or anoxic environment. After reaching desired level ofvitamin E diffusion, the insert is packaged either in air or inert oranoxic environment. The packaged insert is then irradiated to 100 kGydose. The irradiation serves two purposes: (1) crosslinks thepolyethylene and improves wear resistance and (2) sterilizes theimplant.

In this example the polyethylene implant can be any polyethylene medicaldevice including those with abutting interfaces to other materials, suchas metals. An example of this is non-modular, metal-backed, polyethylenecomponents used in total joint arthroplasty.

Example 9 Diffusion of Vitamin E in Polyethylene

An experiment was carried out to investigate the diffusion of syntheticvitamin E (DL-α-tocopherol) into UHMWPE. Consolidated GUR1050 UHMWPE(Perplas Ltd., Lancashire, UK) was machined into 2 cm cubes. The cubeswere immersed in α-tocopherol (Fisher Scientific, Houston, Tex.) fordoping. Doping was carried out in an oven with a nitrogen purge. Cubeswere doped at 25° C., 100° C., 120° C., or 130° C. for 16 hours under0.5-0.6 atm nitrogen pressure, which was applied by first purging theoven with nitrogen, then applying vacuum, and then adjusting the amountof nitrogen (for all except 25° C., which was performed in air atambient pressure). After doping, the samples were rinsed with ethanol toremove excess α-tocopherol from surfaces of the cubes. The extent ofα-tocopherol diffusion into polyethylene was quantified by usinginfrared microscopy and measuring a characteristic absorbance ofα-tocopherol as a function of depth away from a free surface.

The cubes that were doped with α-tocopherol were machined to halves andsectioned (about 100 μm thin sections) using an LKB Sledge Microtome(Sweden). The thin sections were analyzed using a BioRad UMA 500infrared microscope (Natick, Mass.). Infrared spectra were collectedwith an aperture size of 50×50 μm as a function of depth away from oneof the edges that coincided with the free surface of the cube. Thespectra were analyzed by quantifying the absorbance, which is typicallygenerated by vitamin E, namely the absorbance between 1226 and 1275 cm⁻¹wave numbers. The area under the absorbance was integrated andnormalized to the area under the reference absorbance peak, locatedbetween 1850 and 1985 cm⁻¹. The integration of both the vitamin Eabsorbance and the reference absorbance excluded the respectivebaselines. The normalized value is referred to as vitamin E index.

FIG. 1 demonstrates the diffusion profiles of polyethylene cubes thatwere doped at four different temperatures (25° C., 100° C., 120° C. and130° C.). Depth of α-tocopherol diffusion in polyethylene increased withtemperature from 400 μm at 25° C. to 3 mm at 130° C. under ambientpressure.

The diffusion depth and uniformity of the antioxidant, in this exampleof vitamin E, can be varied by varying the doping temperature.

Example 10 Artificial Aging of UHMWPE with and without Vitamin E

An experiment was performed to investigate the effect of vitamin E onthe thermo-oxidative stability of irradiated UHMWPE. Two identicalcylindrical pins (9 mm in diameter and 13 mm in height) were machinedout of a UHMWPE block that was irradiated to 100 kGy with gammaradiation. One base of one of the cylindrical pins was coated withnatural vitamin E (DL-α-tocopherol) and the other pin was left clean.Both pins were then subjected to accelerated aging in an oven at 80° C.in air for 5 weeks. Subsequent to aging, the pins were microtomed toprepare a 200 μm thin section perpendicular to both of the cylindricalbases. Microtomed sections (200 μm each) were then analyzed with aBioRad UMA500 infra-red microscope. Infra-red spectra were collected, asa function of depth away from the edge of the microtomed section, whichcorresponded to the vitamin E exposed cylindrical base. The spectra wereanalyzed by quantifying the carbonyl absorbance between 1680 and 1780cm⁻¹ wave numbers. The area under the absorbance was integrated andnormalized to the area under the reference absorbance peak locatedbetween 1330 and 1390 cm⁻¹. The integration of both the carbonylabsorbance and the reference absorbance excluded the respectivebaselines. The normalized value is referred to as oxidation index.

The clean UHMWPE pin sample showed about six times higher oxidationindex than that of the vitamin E treated pin.

Example 11 Improved Oxidation Resistance with Vitamin E Doping

Compression molded GUR 1050 UHMWPE blocks (Perplas Ltd., Lancashire, UK)(3 inches in diameter) were gamma-irradiated in vacuum to a dose of 111kGy (Steris Isomedix, Northborough, Mass.). Irradiated blocks weremachined into half-cubes of dimensions about 2 cm×2 cm×1 cm.

Four groups of the half-cubes were soaked in α-Tocopherol (α-D,L-T,Fischer Scientific, Houston, Tex.) for doping. The half-cubes of theGroup RT1 were soaked at room temperature for one hour. The half-cubesof the Group RT16 were soaked at room temperature for 16 hour. Thehalf-cubes of the Group 100C1 were soaked at 100° C. for one hour. Thehalf-cubes of the Group 100C16 were soaked at 100° C. for 16 hours.There were a total 3 half-cubes in each group. In addition, three groupsof thermal controls were prepared with three half-cubes in each group.Group TCRT consisted of half-cubes that were machined from one of theirradiated blocks. Group TC100C1 consisted of half-cubes that wereheated to 100° C. for one hour in air. Group TC100C16 consisted ofhalf-cubes that were heated to 100° C. for 16 hours in air.

The soaked and thermal control half-cubes described above were thencleaned in a dishwasher. Cleaning was performed by a portable Kenmoredishwasher (Sears Inc, Hoffman Estates, Ill.) on normal cycle with rinseand heat drying. During cleaning, all half-cube test samples were placedin a cylindrical non-elastic polyethylene mesh of 2 inches in diameterand closed at the ends. This ensured that the samples did not movearound, but the cleaning medium could get through. Electrasol™ (ReckittBenckiser Inc., Berkshire, UK) was used as cleaning agent.

Following cleaning, the samples were subject to accelerated aging todetermine the effect of tocopherol doping under different conditions onthe oxidative stability of the irradiated UHMWPE. Accelerated aging wasperformed by placing the samples in an oven at 80° C. in air for fiveweeks.

Subsequent to aging, the half-cubes were cut in halves and microtomed toprepare a 200 μm thin section perpendicular to one of the 2 cm×2 cmsurfaces. Microtomed sections (200 μm each) were analyzed with a BioRadUMA500 infra-red microscope. Infra-red spectra were collected, as afunction of depth away from the edge of the microtomed section, whichcorresponded to the surface that was soaked in tocopherol and alsoexposed to air during aging. The spectra were analyzed by quantifyingthe carbonyl absorbance between 1680 and 1780 cm⁻¹ wave numbers. Thearea under the absorbance was integrated and normalized to the areaunder the reference absorbance peak located between 1330 and 1390 cm⁻¹.The integration of both the carbonyl absorbance and the referenceabsorbance excluded the respective baselines. The normalized value isreferred to as oxidation index.

Maximum oxidation values of each microtomed sections was calculated andaverages of three sections from each Group described above are shown inTable 1. Thermal control for 111 kGy-irradiated, cleaned and agedsamples for UHMWPE doped with tocopherol at room temperature showed highlevels of oxidation. The average maximum oxidation levels in irradiated,tocopherol doped, cleaned, and aged samples for durations of 1 hour and16 hours, respectively, were lower than their respective thermalcontrols that were not doped but had the same thermal history.

Thermal control (Group TC100C1) for 111 kGy irradiated, cleaned and agedsamples for UHMWPE doped with tocopherol at 100° C. for 1 hour showedhigher levels of oxidation than the corresponding tocopherol doped testsamples (Group 100C1). Similarly, thermal control (Group TC100C16) for111 kGy irradiated, cleaned and aged samples for UHMWPE doped withtocopherol at 100° C. for 16 hours showed higher levels of oxidationthan the tocopherol doped test samples (Group 100C16). The oxidationlevels of the thermal controls and test samples did not show significantdifference between a soak time of 1 hour and 16 hours. The oxidationlevels for doped samples at 100° C. were less than those doped at roomtemperature. TABLE 1 Maximum oxidation values for cleaned andaccelerated aged control and tocopherol doped 111 kGy irradiated UHMWPE(RT denotes that doping was done at room temperature). Sample ID AverageMaximum Oxidation Index Group TCRT 3.68 ± 0.15 Group RT1 0.38 ± 0.05Group RT16 0.40 ± 0.03 Group TC100C16 0.97 ± 0.04 Group 100C1 0.098 ±0.003 Group TC100C1 0.70 ± 0.18 Group 100C16 0.080 ± 0.003

FIG. 2 shows the oxidation index profile as a function of depth into oneof the representative aged cubes of each group studied (Group TCRT,Group RT1, Group RT16, Group TC100C16, Group 100C1, Group TC100C1, andGroup 100C16).

These results show that cleaning by washing and drying did not removethe tocopherol diffused into UHMWPE and tocopherol was able to protectagainst oxidation of high-dose irradiated UHMWPE under aggressive agingconditions.

Example 12 Ionizing Sterilization of Balloon Catheters

The increased use of drug coatings on balloons and stents precludes theuse of ethylene oxide sterilization in many cases. Additionally,improved wear behavior is desired for balloons that are used to inflatemetallic stents. Polyethylene balloons are soaked in vitamin E at roomtemperature and pressure for 16 hours. The balloons are then exposed toionizing radiation in dose levels ranging from 25 kGy to 100 kGy. Theradiation sterilizes the component without affecting the drug, andcrosslinks the polyethylene to improve the wear behavior. Oxidationresulting from residual free radicals can be minimized by the presenceof the vitamin E.

Example 13 Improved Oxidation Resistance of Packaging Material

Packaging made from polyethylene films is soaked in vitamin E at roomtemperature and kept under pressure for 16 hours. The packaging is thensterilized by ionizing radiation at doses 25-40 kGy. The packaging isprotected from oxidation-induced embrittlement, which can affect boththe mechanical integrity and the gas barrier properties of thepackaging.

Example 14 Irradiation and Doping of UHMWPE

Cubes (20 mm to a side) were machined from three different bar stocksmade out of GUR1050 UHMWPE that are treated as follows: (1) gammairradiated to 65 kGy, (2) gamma irradiated to 100 kGy, and (3)unirradiated. The cubes were than doped by soaking in vitamin E(DL-α-tocopherol) for 16 hours at room temperature. Two groups of cubes,one machined from the 65 kGy and the other from the 100 kGy irradiatedstocks, were packaged following doping with vitamin E and irradiatedagain with gamma irradiation for sterilization at a dose level of 25-40kGy. One additional group of cubes, machined from unirradiated stock,was packaged following doping with vitamin E and irradiated again withgamma irradiation for crosslinking and sterilization at a dose level of125-140 kGy.

Example 15 The Pin-On-Disk (POD) Wear Behavior of Irradiated and VitaminE Doped UHMWPE Before and After Aging

Consolidated GUR 1050 UHMWPE bar stocks were gamma irradiated at 65 kGyand 100 kGy. Cylindrical pins (9 mm in diameter and 13 mm in length)samples for POD wear testing were machined from the irradiated barstocks. The samples were doped with vitamin E (α-Tocopherol) for 16hours at room temperature in air. Following doping, the samples werefurther gamma sterilized at a dose of 27 kGy. These two groups arereferred to as α-T-92 and α-T-127 with a total radiation doses of 92 kGyand 127 kGy, respectively.

Half of the cylindrical samples were subjected to accelerated aging at80° C. in air for five weeks. Both un-aged and aged samples weresubjected to POD wear testing. The wear behavior of the pins was testedon a custom-built bi-directional pin-on-disc wear tester at a frequencyof 2 Hz by rubbing the pins against an implant-finish cobalt-chromecounterface in a rectangular wear path (Muratoglu et al., Biomaterials,20(16):1463-1470, 1999). The peak contact stress during testing was 6MPa. Bovine calf serum was used as lubricant and quantified weargravimetrically at 0.5 million-cycle intervals. Initially, the pins weresubjected to 200,000 cycles of POD testing to reach a steady state wearrate independent of diffusion or asperities on the surface. Thereafter,three pins of each group were tested for a total of 2 million cycles.The wear rate was calculated as the linear regression of wear vs. numberof cycles from 0.2 to 2 million cycles. The wear rates of doped and agedcross-linked polyethylenes are shown in Table 2. TABLE 2 The wear rateof doped and aged cross-linked polyethylene. Wear rate Wear rate(milligrams/million (milligrams/million Sample ID cycles) before agingcycles) after aging α-T-92 (65 kGy +  1.5 ± 0.3  1.9 ± 0.5 doping + 27kGy) α-T-127 (100 kGy + 0.82 ± 0.2 0.91 ± 0.1 doping + 27 kGy)

The wear behavior of the doped samples were comparable before and afteraging, indicating that the presence of an antioxidant incorporated bydiffusion can protect the irradiated polyethylene from oxidation andthus prevent an increase in wear after aging. Typically the wear rate ofa 100 kGy irradiated UHMWPE is around 1 milligrams per million-cycle(Muratoglu et al., Biomaterials, 20(16):1463-1470, 1999). Aging of an105 kGy irradiated UHMWPE can increase its wear rate to above 20milligram/per cycle (Muratoglu et al. Clinical Orthopaedics & RelatedResearch, 417:253-262, 2003).

Example 16 Oxidation Stabilization of Polyether-Block Co-PolyamideBalloons

Balloons fabricated from polyether-block co-polyamide polymer (PeBAX®)are sterilized with either gamma or electron beam after packaging. Asthere is concern about oxidative embrittlement of these materials due tofree radical generation, quenching of the free radicals is imperative toensure an extended shelf life (for example, a three-year shelf life).These materials cannot be heat-treated following irradiation, given thatthe highly aligned polymer chains relax when exposed to elevatedtemperatures, resulting in radial and axial shrinkage.

Polyether-block co-polyamide balloons are soaked in vitamin E, or in asolution of vitamin E and a solvent such as an alcohol. The balloons arepackaged, and then subjected to sterilization doses ranging from 25-70kGy. The higher radiation dose results from double sterilization doses.Sterilization can occur either in air or in a low oxygen atmosphere. Thevitamin E minimizes the oxidative behavior of residual free radicalsintroduced during the sterilization process and also can reduceundesired crosslinking.

Example 17 Oxidation Stabilization of Nylon Balloons

Balloons fabricated from Nylon polymer are sterilized with either gammaor electron beam after packaging. As there is concern about oxidativeembrittlement of these materials due to free radical generation,quenching of the free radicals is imperative to ensure a three yearshelf life. These materials cannot be heat-treated followingirradiation, given that the highly aligned polymer chains relax whenexposed to elevated temperatures, resulting in radial and axialshrinkage.

Nylon balloons are soaked in vitamin E, or in a solution of vitamin Eand a solvent such as an alcohol. The balloons are packaged, and thensubjected to sterilization doses ranging from 25-70 kGy. The higherradiation dose results from double sterilization doses. Sterilizationcan occur either in air or in a low oxygen atmosphere. The vitamin Eminimizes the oxidative behavior of residual free radicals introducedduring the sterilization process and also can reduce undesiredcrosslinking.

Example 18 Oxidation Stabilization of Polyethylene TerephthalateBalloons

Balloons fabricated from polyethylene terephthalate (PET) polymer aresterilized with either gamma or electron beam after packaging. As thereis concern about oxidative embrittlement of these materials due to freeradical generation, quenching of the free radicals is imperative toensure an extended shelf life (for example, a three-year shelf life).These materials cannot be heat-treated following irradiation, given thatthe highly aligned polymer chains relax when exposed to elevatedtemperatures, resulting in radial and axial shrinkage.

PET balloons are soaked in vitamin E, or in a solution of vitamin E anda solvent such as an alcohol. The balloons are packaged, then subjectedto sterilization doses ranging from 25-70 kGy. The higher radiation doseresults from double sterilization doses. Sterilization can occur eitherin air or in a low oxygen atmosphere. The vitamin E minimizes theoxidative behavior of residual free radicals introduced during thesterilization process and also can reduce undesired crosslinking.

Example 19 Oxidation Stabilization of Multi-Component Balloons

Multi-component balloons fabricated from a combination of polymers,including polyethylene, PET, polyether-block co-polyamide, polyvinylacetate, and nylon, are sterilized with either gamma or electron beamafter packaging. As there is concern about oxidative embrittlement ofthese materials due to free radical generation, quenching of the freeradicals is imperative to ensure an extended shelf life (for example, athree-year shelf life). These materials cannot be heat-treated followingirradiation, given that the highly aligned polymer chains relax whenexposed to elevated temperatures, resulting in radial and axialshrinkage.

These multi-component balloons are soaked in vitamin E, or in a solutionof vitamin E and a solvent such as an alcohol. The balloons arepackaged, and then subjected to sterilization doses ranging from 25-70kGy. The higher radiation dose results from double sterilization doses.Sterilization can occur either in air or in a low oxygen atmosphere. Thevitamin E minimizes the oxidative behavior of residual free radicalsintroduced during the sterilization process, and also can reduceundesired crosslinking.

Example 20 Sterilization of Polypropylene Medical Devices

Polypropylene is widely used in the medical industry to producesyringes, vials, and numerous other devices, often through injectionmolding. Polypropylene is known to exhibit oxidative degradation when itis subjected to ionizing sterilization with gamma or electron beam orgas sterilization with ethylene oxide or gas plasma.

Polypropylene syringes are soaked in vitamin E, or in a solution ofvitamin E and a solvent such as an alcohol. The syringes are packaged,and then subjected to sterilization doses ranging from 25-70 kGy. Thehigher radiation dose results from double sterilization doses.Sterilization can occur either in air or in a low oxygen atmosphere. Thevitamin E will minimizes the oxidative behavior of residual freeradicals introduced during the sterilization process, and could alsoreduce undesired crosslinking.

Example 21 Sterilization of Flexible Polyvinyl Chloride Tubing

Flexible polyvinyl chloride (PVC) is used in a variety of medicaldevices, including tubing. While previously sterilized with ethyleneoxide, more manufacturers are using gamma or electron beam to sterilize.Upon exposure to ionizing radiation, these material often darken andyellow, which is believed to be due to oxidation (Medical Plastics andBiomaterials Magazine, March, 1996, Douglas W. Luther and Leonard A.Linsky). Yellowing is reduced when antioxidants are compounded into thePVC with a mechanical mixer or extruder.

PVC tubing is soaked in vitamin E, or in a solution of vitamin E and asolvent such as an alcohol. The tubing is then subjected tosterilization doses ranging from 25-70 kGy. The higher radiation doseresults from double sterilization doses. Sterilization can occur eitherin air or in a low oxygen atmosphere. The vitamin E minimizes theoxidative behavior of residual free radicals introduced during thesterilization process, and results in color-stabilized PVC components,as well as improved shelf life.

Example 22 Annealing After Doping

Post-doping annealing can be used to achieve a more uniform antioxidantdistribution. Unirradiated UHMWPE cubes were doped at 130° C. for 96hours by soaking in undiluted α-tocopherol. One cube was machined inhalves and microtomed. The microtomed sections were analyzed usinginfra-red microscopy, as described above in Example 9, to measure thevitamin E index as a function of depth away from one of the surfacesthat was free during doping. Subsequent to doping, other doped cubeswere annealed at 130° C. for increasing periods of time. The doped andannealed cubes were also analyzed using the infrared microscope todetermine the changes on the vitamin E index profile as a function ofannealing time. FIG. 3 shows the diffusion profiles measured in thedoped and also doped and annealed cubes. In the sample that has not beenannealed, the surface concentration was much higher than that for thebulk, but the sample that had been annealed for 100 hours at the sametemperature showed a nearly uniform profile. Therefore, annealing afterdoping can be used to increase the uniformity of the antioxidantdistribution throughout the host polymer. The temperature and time ofannealing can be tailored by carrying out a parametric analysis asdescribed herein.

Example 23 Sequences of Processing UHMWPE

UHMWPE can be doped with antioxidants at various stages, for example, asschematically shown in FIGS. 4 and 5.

Example 24 Post-Doping Annealing in Boiling Water

UHMWPE was irradiated to 100 kGy with gamma irradiation. Six cubes (20mm to a side) were machined from the irradiated UHMWPE. The cubes werethen soaked in vitamin E (α-tocopherol) at various temperatures. Twocubes were soaked in 100° C. vitamin E for 24 hours, two other cubeswere soaked in 105° C. vitamin E for 24 hours, and the remaining twocubes were soaked in 110° C. vitamin E for 24 hours. Following thevitamin E doping step, one cube of each temperature group was cut inhalf and a 200 μm thin section was microtomed. The thin section was thenanalyzed using a BioRad UMA 500 infra-red microscope as a function ofdistance away from the edge that corresponded to one of the surfaces ofthe cube that was exposed to vitamin E during doping. The other cubes ofeach temperature group were soaked in boiling water for 24 hours.Subsequently, these boiling water soaked cubes were also microtomed andanalyzed with the infra-red microscope as described above. The infra-redspectra collected from the thin sections were analyzed to calculate asensitive vitamin E index (sensVitE), defined as:sensVitE=(Area under the absorbance peak with limits of 1245 to 1275cm⁻¹) divided by (Area under the absorbance peak with limits of 1850 to1985 cm⁻¹).

The absorbance peak bound by the wave numbers 1245 and 1275 cm⁻¹ is acharacteristic peak of vitamin E. The intensity of this absorbance peakincreases with increasing vitamin E content in UHMWPE.

The depth-profiles of sensVitE for each cube are shown in FIGS. 6A and6B. FIG. 6A depicts vitamin E profiles obtained in vitamin E doped cubesthat were machined from a 100 kGy irradiated UHMWPE (solid marks) andthe vitamin E profiles of the doped cubes after annealing in boilingwater (hollow marks). Annealing in boiling water improved thepenetration depth of the vitamin E into irradiated UHMWPE (see FIG. 6A).

FIG. 6B shows the vitamin E penetration profiles at a higher resolution.Results indicate that the 105° C. 24 hour doped and 24 hour 100° C.exhibited more penetration than the 105° C. 48 hours doped sample, eventhough both were at an elevated temperature between 100-105° C. for atotal of 48 hours.

Example 25 Doping of Irradiated UHMWPE in Vitamin E Emulsion

Two UHMWPE stock materials were irradiated to 100 and 110 kGy with gammairradiation. Four cubes (20 mm to a side) were machined from theirradiated UHMWPE stock materials. One cube (100 kGy) were then soakedin a mixture of 30% vitamin E (α-tocopherol) and 70% deionized water at100° C. for 24 hours. The remaining three cubes (110 kGy) were soaked in100% vitamin E at about 100° C. One cube was removed from the 100%vitamin E bath after 24, 50, and 72 hours of soaking. Following thedoping steps, all cubes were cut in half and a 200 μm thin section wasmicrotomed. The thin sections were then analyzed using a BioRad UMA 500infra-red microscope as a function of distance away from the edge thatcorresponded to one of the surfaces of the cube that was exposed tovitamin E or vitamin E emulsion during doping. The infra-red spectracollected from the thin sections were analyzed to calculate a sensitivevitamin E index (sensVitE).

The depth-profiles of sensVitE are shown in FIGS. 7A and 7B. FIG. 7-Adepicts vitamin E profiles obtained from the 24 hour doped cubes. Dopingat 100° C. in the vitamin E emulsion resulted in a higher vitamin Esurface concentration and a deeper vitamin E penetration than the cubethat was doped in 100% vitamin E. FIG. 7B shows the vitamin E profilesof cubes doped for various time periods. Doping at 100° C. in vitamin Eemulsion resulted in a diffusion profile equivalent to 72 hours ofdoping in 100% vitamin E at 100° C. Therefore, doping in an emulsion ofvitamin E is more effective than doping in pure vitamin E.

Example 26 Doping of Irradiated UHMWPE Followed by Annealing in BoilingWater or in Boiling NaCl Aqueous Solution

UHMWPE stock material was irradiated to 100 kGy with gamma irradiation.Three cubes (20 mm to a side) were machined from the irradiated UHMWPEstock materials. All three cubes were then soaked in 100% vitamin E(α-tocopherol) at 105° C. for 24 hours. One of the cubes was then cooleddown to room temperature and soaked in boiling 8 molar aqueous,sodium-chloride solution in a reflux chamber for 24 hours. One of theremaining two cubes was soaked in boiling deionized water in a refluxchamber for 24 hours. The third cube was not treated after the initialvitamin E doping step. All three cubes were then cut in half and a 200μm thin section was microtomed. The thin sections were then analyzedusing a BioRad UMA 500 infra-red microscope as a function of distanceaway from the edge that corresponded to one of the surfaces of the cubethat was exposed to vitamin E or vitamin E emulsion during doping. Theinfra-red spectra collected from the thin sections were analyzed tocalculate a sensitive vitamin E index (sensVitE).

The depth-profiles of sensVitE are shown in FIG. 8. The depth ofpenetration of vitamin E increased with the post-doping annealing inboiling water; same was true when the boiling NaCl solution was used.The surface concentration of vitamin E was with the boiling NaClsolution than it was with boiling water. Annealing of vitamin E dopedUHMWPE in boiling water is beneficial in increasing the depth ofpenetration of vitamin E. Similarly, annealing of vitamin E doped UHMWPEin boiling NaCl aqueous solution is beneficial in increasing the depthof penetration of vitamin E. Annealing of vitamin E doped UHMWPE inboiling NaCl aqueous solution is more beneficial in keeping the surfaceconcentration of vitamin E higher while also increasing the depth ofpenetration of vitamin E.

It is to be understood that the description, specific examples and data,while indicating exemplary embodiments, are given by way of illustrationand are not intended to limit the present invention. Various changes andmodifications within the present invention will become apparent to theskilled artisan from the discussion, disclosure and data containedherein, and thus are considered part of the invention.

1-89. (canceled)
 90. A method of making a medical implant comprisingnon-oxidizing cross-linked ultrahigh molecular weight polyethylene(UHMWPE) containing detectable residual free radicals, wherein themethod comprises: a) compression molding the UHMWPE to another piece,thereby forming an interface and an interlocked hybrid material; b)doping the interlocked hybrid material with an antioxidant by diffusionin a supercritical fluid at 105° C. for 24 hours; d) annealing theantioxidant-doped interlocked hybrid material in boiling water underatmospheric pressure for 100 hours at 100° C.; e) irradiating theinterlocked hybrid material by ionizing radiation at a dose of 100 kGy,thereby forming a medical implant having interlocked hybrid materialcomprising non-oxidizing cross-linked UHMWPE containing detectableresidual free radicals, wherein the irradiation is carried out in avacuum; (f) packaging the medical implant having interlocked hybridmaterial comprising non-oxidizing cross-linked UHMWPE containingdetectable residual free radicals; and (g) sterilizing the packagedantioxidant-doped cross-linked medical implant by ionizing radiation orgas sterilization, thereby forming a sterile, oxidation-resistant, andcross-linked medical implant, wherein the implant comprises medicaldevices selected from the group consisting of acetabular liner, shoulderglenoid, patellar component, finger joint component, ankle jointcomponent, elbow joint component, wrist joint component, toe jointcomponent, bipolar hip replacements, tibial knee insert, tibial kneeinserts with reinforcing metallic and polyethylene posts, intervertebraldiscs, sutures, tendons, heart valves, stents, and vascular grafts.